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ROLE OF CHEMOTHERAPY IN IMPROVING DYSPHAGIA FREE SURVIVAL IN PATIENTS WITH ADVANCED ESOPHAGEAL CANCER TREATED WITH HIGH DOSE RATE BRACHYTHERAPY ROLE OF CHEMOTHERAPY IN IMPROVING DYSPHAGIA FREE SURVIVAL IN PATIENTS WITH ADVANCED ESOPHAGEAL CANCER TREATED WITH HIGH DOSE RATE BRACHYTHERAPY By EMILIA OLIMPIA TIMOTIN, BSc A Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements for the Degree of Master of Science McMaster University II Master of Science (Medical Physics and Applied Biology) McMaster University Hamilton, Ontario Title Role of Chemotherapy in Improving Dysphagia Free Survival in Patients with Advanced Esophageal Cancer Treated with High Dose Rate Brachytherapy Author Emilia Olimpia Timotin Supervisor Dr. Ranjan K Sur Dr. Thomas Farrell Number of Pages 104 III ABSTRACT BACKGROUND High dose rate Intraluminal Brachytherapy (HDRILBT) is one of the most used palliative treatment options for advanced esophageal cancer. The present study evaluates the role of additional chemotherapy in improving dysphagia free survival (DFS) and overall survival (OS) in patients with inoperable advanced esophageal cancer treated with brachytherapy. MATERIAL and METHODS 132 patients with advanced metastatic esophageal cancer with total or near total dysphagia were given HDRILBT to a dose of 18 Gray (Gy) in 3 fractions on alternate days. Intraluminal brachytherapy alone was performed on 98 patients. 34 patients received Epirubicin, 5-Fluorouracil, and Cisplatin (ECF) chemotherapy regimen after HDRILBT. The mean age of the whole group was 65 years (HDRILBT-71.41, HDRILBT+ECF-59.98; p<0.0001). Male: Female was 101:31 (HDRILBT 72:26; HDRILBT +ECF 29:5; p>0.05). The location incidence was GEJ: Lower Esophagus: Mid Esophagus: Cervical Esophagus 24:81:17:5 respectively; for the whole group HDRILBT17:57:16:4; HDRILBT+ECF-7:24:1:1; p>0.05. 78 patients presented with co-morbidities (cardiac) (HDRILBT- 59; HDRILBT+ECF- 19; p>0.05). 74 patients presented with distant metastasis (54 with HDRILBT and 20 with HDRILBT+ECF; p>0.05). The ECOG scores were as follows 0:1:2:3:4 15:52:51:12:2 (HDRILBT- 10:35:41:10:2; HDRILBT+ECF- 5:17:10:2:0; p=0.0014). All patients completed 3 fractions of HDRILBT. 34 patients received additional chemotherapy with ECF regimen. Selection of patients was done by the medical oncologist. Statistical analysis of data was done using the SAS statistical analysis software system. Univariate and multivariate analysis was done using the log rang test. IV RESULTS Patients who received additional ECF were younger (p< 0.001) and with a better performance status than those who received HDRILBT alone (p=0.0014). Mean DFS was higher for patients who had further chemotherapy treatment (232 days) vs. patients who had HDRILBT only (155 days) (p>0.05). The mean OS for HDRILBT + ECF was 266 days (p = 0.0010) compare with HDRILBT alone which was 155 days, when the effect of 10 prognostic factors was analyzed for DFS and OS. Only additional ECF after brachytherapy impacted on DFS while age (p<0.001) and performance status (p=0.0014) impacted on overall survival on univariate analysis. On multivariate analysis tumor length and nodal presentation (p<0.000) impacted on OS. The incidence of stricture and fistulae were similar. Chemotherapy related side effects: gastrointestinal tract (25 patients), neurotoxicities (2) and nephrotoxicities (2) were seen as a result of 5-FU and Cisplatin respectively. 18 patients completed at least 3 cycles of ECF. CONCLUSION Additional chemotherapy with ECF after HDRILBT improves the DFS and OS in selected patients with advanced esophageal cancer. These patients tend to be younger with better performance status, small tumor length and nodal metastasis. The incidence of complications is similar with more than 50% patients completing at least 3 cycles of chemotherapy. V ACKNOWLEDGEMENTS I would never have been able to finish my thesis without the guidance of my committee members, help from friends, and support from my family. First and foremost I would like to express my deepest gratitude to my advisor, Dr. Ranjan K. Sur. Without his vision and initiative, this research would have not been done. I am thankful for his aspiring guidance, invaluably constructive criticism and friendly advice during the project work. Many thanks for offering me the opportunity to conduct this study, for his excellent guidance, for mentoring me throughout this endeavor, for his enthusiasm. Nonetheless my gratitude goes to my supervisor Dr. Thomas Farrell for sharing his truthful and illuminating views on a number of issues related to the project. I am grateful that he provided the necessary support for me to gain confidence in myself. I am sincerely grateful to him for patiently corrected my writing, for his motivation, insightful comments, support and immense knowledge. As always, for believing in me and for her support, my sincere appreciation goes to my manager Marcia Smoke. I would also like to thank Bernard Donde for his help and guidance in data analysis. Special thanks go to Dr. Colin Seymour who was willing to participate in my final defense committee at the last moment. I would like to thank Christine Pinho, who as a good friend was always willing to help and give her best suggestions. It would have been a lonely work without her. Many thanks to my colleagues and friends at work especially Michele Cardoso and Lilian DoerwaldMunoz who contributed with encouraging words and comforting words and kept me going. My research would not have been possible without their help. Last but not least, I would like to offer my deeply thanks to my husband and two children Antonia and Titus for their patience and tremendous help during this time. They were always supporting me and encouraging me with their best wishes. Thank you for being there for me throughout my life and supporting my every decision. VI TABLE OF CONTENTS Abstract iv Acknowledgments vi Table of Contents vii List of Illustrations, Chart, and Diagrams ix List of Abbreviations, and Symbols xii 1.0 Introduction 1.1 Esophageal cancer 1 1.1.1 Incidence and Mortality in North America and Worldwide 3 1.1.2 Risk Factors 6 1.1.3 Pathology 10 1.1.4 Presentation 11 1.1.5 Factors Affecting Prognosis 12 1.1.6 Diagnostic Work-up 13 1.1.7 Assessment and Staging 15 1.2 Treatment Options 19 1.3 Objectives and Aims 22 1.4 Hypotheses of the Study 23 1.5 Review of Literature 24 VII 1.5.1 The role of brachytherapy in palliation of dysphagia 25 1.5.2 The role of chemotherapy in metastatic esophageal cancer 33 2.0 Patients and Methods 52 3.0 Results 62 4.0 Discussion 77 5.0 Conclusion 81 6.0 Reference List 82 VIII LIST OF FIGURES AND TABLES Figure 1.1 Anatomy of the esophagus Figure 1.1.6.1 Advanced esophageal cancer: A, Near total obstruction; B, Barium swallow x-ray 14 Figure 1.1.7.1 Esophageal Cancer Staging 15 Figure 2.8 Remote Afterloader Brachytherapy Unit 55 Figure 2.9 Barium swallow examination of an complete tumor obstracted esophagus 55 Figure 2.10 Localization of Intra-oral tube/Catheter in situ 56 Figure 2.11 Marker wire used to measure the tumor length. 57 Figure 2.12 Diagram showing definition of the target volume 57 Figure 2.13 Treatment Plan Distributions 58 Figure 3.1 Pie graph showing age distribution of patients 65 Figure 3.2 Pie graph showing gender distribution of patients 66 Figure 3.3 Pie graphs showing male and female distribution of patients studied for each treatment strategy 66 Figure 3.4 Pie graph showing tumor location 67 Figure 3.6 Pie graph showing tumor pathology 68 Figure 3.7 Distribution of Nodal Metastasis for patient receiving HDRILBT only 69 Figure 3.8 Distribution of Nodal Metastasis for patient receiving HDRILBT plus Chemotherapy 69 IX 1 Figure 3.9 Distant Metastases 70 Figure 3.10 Distribution of treatment given and number of patients 71 Figure 3.12 Dysphagia Free Survival DFS 72 Figure 3.13 Overall Survival OS 74 Table 1.1.2.1 Esophageal cancer risk factors Table 1.1.4.1 Dysphagia Grading 11 Table 1.1.7.2 TNM 7th Edition of the AJCC Cancer Staging Manual: 17 6 Esophagus and Esophagogastric Junction Table 1.1.7.3A 7th Edition of the AJCC Cancer Staging Manual; Adenocarcinoma stage grouping 18 Table 1.1.7.3B 7th Edition of the AJCC Cancer Staging Manual; Squamous-cell carcinoma stage groupings 18 Table 1.2.1 Palliative Treatment Methods for Advanced Esophageal Cancer 19 Table 1.2.2 Methods of Palliation and Median Survival 21 Table 1.2.3 Comparison between treatment modalities for dysphagia relief 21 Table 1.5.1.1 High Dose Rate Brachytherapy – Palliative Results 26 X Table 1.5.2.1 Old single chemotherapy agents 34 Table 1.5.2.2 New single chemotherapy agents 37 Table 1.5.2.3 Combination of two chemotherapy agents 45 Table 2.1 EORTC-QLQ 53 Table 2.2 Dysphagia algorithm 54 Table 2.3 Clinical Patient Characteristics 62 Table 2.4 Tumor Characteristics and Treatment Features 63 Table 2.6 WHO/ECOG 64 Table 2.7 Study Patients’ Performance Status 64 Table 3.5 Tumor Pathology 68 Table 3.11 Dysphagia free survival for both treatment modalities 72 Table 3.14 Overall survival for both treatment modalities 74 Table 3.15 Complications for both treatment modalities 76 Table 3.16 Total numbers of toxicities for both treatment modalities together 76 Review HDRILBT with literature 77 Table 4.1 XI LIST OF ABREVIATIONS HDRILBT High Dose Rate Intraluminal Brachytherapy ECF Epirubicin, Cisplatin, 5- Fluorouracil EORTC-QLQ European Organization for Research and Treatment of Cancer Quality of Life Questionnaire WHO World Health Organization ECOG Eastern Cooperative Oncology Group DFS Dysphagia Free Survival OS Overall Survival SCC Squamous Cell Carcinoma AC Adenocarcinoma CT Computed Tomography PET Positron Emission Tomography EUS Endoscopic Ultrasound HRQoL Health Related Quality of Life GEJ Gastro-esophageal Junction XII 1.0 INTRODUCTION 1.1 ESOPHAGEAL CANCER The esophagus is a long hollow tubed organ that is lined with stratified squamous epithelium and has the main function of passing food from the mouth to the stomach. Several layers of tissue make up the wall: the mucosal layer, submucosal layer, muscular layer and the adventitia layer (Figure 1.1). The uncontrolled division of abnormal cells leads to cancer. This cell growth and development remains unregulated and will develop into a tumor. The cells can enter the blood stream or lymphatic system and as a result can spread to other organs. This process is known as metastasis. Figure 1.1 - Anatomy of the esophagus [3] 1 Esophageal cancer is a gastrointestinal malignant tumor that forms in esophagus tissue. It has an insidious onset and a poor prognosis. On average, for tumors under 5cm long, 30% are localized, 40% are locally advanced and 30% have undergone metastasis [19]. For tumors longer than 5cm, 10% remain localized, 25% become locally advanced and 70% undergone distant metastasis [19]. The spread occurs from the inside of the esophagus, outwards through several layers of tissue. Among many presenting symptoms experienced by patients, dysphagia is the most predominant. Dysphagia is defined as difficulty in swallowing caused by a lesion or a stricture, leading to an obstruction of the esophagus by a tumor. When dysphagia to solid food occurs, the esophagus is almost completely obstructed with 90% of the lumen compromised and the muscularis mucosa has been penetrated by the tumor into the adventitia. One of the major concerns with esophageal cancer is the poor prognosis in the majority of cases. Almost all patients have advanced disease at the time of initial consultation [19]. 2 1.1.1 INCIDENCE AND MORTALITY IN ESOPHAGEAL CANCER IN NORTH AMERICA AND WORLDWIDE INCIDENCE AND MORTALITY IN NORTH AMERICA The incidence of esophageal cancer has been steadily increasing over the past decades worldwide [19]. In North America in 2013 the incidence of new cases of esophageal cancer was estimated to be around 2000 from all Canadians [22]. The number of Canadians with esophageal cancer who will die from the disease has been approximated to be around 1900 [22]. Annually this number has been increasing at a steady rate with a change in histologic type of esophageal cancer and the location of the primary tumor [19]. Esophageal cancer is amongst the 10 most common causes of cancer death in men with an estimated percentage of 5-7%. A five-year relative survival rate is approximately 38% when the disease is localized, 20% for regional and 3% for metastasis. These survival rates for esophageal cancer pertain to squamous cell carcinomas and adenocarcinomas together [142]. Esophageal cancer can be either squamous cell carcinoma or adenocarcinoma. The most common histological form of cancer in the esophagus has long been the squamous cell carcinoma type. For the last ten years, reports have shown a rising incidence of esophageal adenocarcinoma in most of the western world, and an unchanged percentage in Asia and South America [122]. It had been largely thought that esophageal adenocarcinoma, for the most part, did not exist until the 1950's. Lately it has been one of the fastest growing cancers in America [116, 97, 2]. For different types of esophageal cancer, squamous cell carcinoma has been seen commonly in blacks and white women while adenocarcinoma among white men. The primary tumor location was more frequently in the distal esophagus. Squamous cell carcinoma occurred mostly in the upper third or middle of the esophagus. Adenocarcinomas were predominant in lower third of the esophagus and gastroesophageal junction [24, 50]. 3 The incidence rates have increased from 1996 to 2009 by 0.5% in all races. This has happened because of an increased incidence in men. In woman, the incidence actually had dropped by 0.4% [99]. The incidence of blacks have been shown to be twice that of whites (8.63/100000 vs. 4.39/100000, p<0.05) [35]. Esophageal cancer has occurred 3-4 times more often in males than females [24, 50]. Keighley study showed the same result with male to female ratio of 3 to 1 [74]. In Asia men and women ratio had been almost equal [75]. As per Canadian Cancer Society statistics, in Canada it was estimated that 1,550 men and 460 women were diagnosed with esophageal cancer in 2013 [22]. The risk of esophageal carcinoma, for both squamous cell carcinomas and adenocarcinomas, has increased with age. The mean age at diagnostic was seen to be 67 years [35]. Esophageal cancer is seen all around the world. The geographic difference in cancer of the esophagus suggests that the environmental exposure plays an important role. Blot et al showed that squamous cell carcinoma is the most frequent histological type of esophageal cancer. Additionally, they concluded that the incidence of adenocarcinoma of the esophagus and esophagogastric junction has been rising especially in US and Europe among white men [12]. The same conclusion was confirmed by studies of Pera et al. They reported a shift in the histology of esophageal cancer in the western countries and the location of the tumor being more frequent in the distal esophagus [105]. In contrary, it was seen an unchanged incidence in this matter in Asia [47] and South America [44]. In 90% of cases of esophageal cancer in central Asia to North - Central China, squamous cell carcinomas had been predominant [54, 134]. Furthermore, it was observed an incidence pattern change because of immigrants that are adjusting correspondingly to where they live [135]. 4 INCIDENCE AND MORTALITY WORLDWIDE The top five cancers that kill are lung, colon, breast, prostate and pancreas. Cancer related deaths are liver cancer at 3%, ovarian cancer with 2.7%, esophageal cancer having 2.4%, bladder cancer 2.4% and brain cancer with 2.3% incidence rates. In combination, these account for 69.1% of all deaths related to cancer [122]. Esophageal cancer is detected in approximately half a million people every year worldwide and the incidence is increasing unfortunately very fast [103]. It is the eighth most common cancer and the sixth most common cause of cancer death [101]. Surgical removal is no longer a viable treatment strategy for more than half of patients diagnosed with an advanced stage of esophageal cancer [116]. It also has been reported that the majority of esophageal cancer cases (80-85%) are diagnosed in developing countries; the predominant type is squamous cell carcinoma and it is the fourth most common cancer in men [18]. Incidence rates vary worldwide by about 16-fold where South and East Africa and East Asia are at the highest and Western and Middle Africa and Central America is the lowest [24, 50]. Worldwide, the survival rate of the esophageal cancer patient is poor because of advanced or inoperable disease at presentation. The disease has very aggressive nature and less than 15% of patients survive 5 years after initial diagnosis [74]. 5 1.1.2 RISK FACTORS The recognized main risk factors for esophageal cancer in general are smoking, excessive alcohol consumption, dietary factors mostly red meat consumption, gastro-esophageal reflux disease (GERD) and Barett’s esophagus [136] (Table 1.1.2.1). Lifestyle factors are associated with a risk of mucosal irritation and could promote tumor formation [34]. Table 1.1.2.1 - Esophageal cancer risk factors [42] RISK FACTOR SQUAMOUS CELL ADENOCARCINOMA CARCINOMA Smoking +++ ++ Alcohol consumption +++ Red meat consumption + + Barnett’s esophagus ++++ Reflux symptoms +++ Being overweight ++ Poverty ++ Caustic injury to the esophagus ++++ History of head and neck cancer ++++ History of radiotherapy +++ +++ Hot drinks consumption + -: No effect; +: Suspicious effect; ++: Positive effect; +++, ++++: Strong positive effect. SMOKING AND ALCOHOL Cigarette smoking had been long correlated with squamous cell carcinoma of the esophagus. A study reported that smoking and alcohol if consumed alone, it accounted for 87% of squamous cancers but if they were mixed they accounted for 50% of adenocarcinomas [138]. Lately, there were studies that correlated smoking with gastroesophageal adenocarcinomas [125]. Sung et al. reported that the combination of cigarette and alcohol was associated with both squamous cell carcinoma and adenocarcinoma of esophagus, cardia, and proximal and distal gastric cancers. Engel and co-workers stated 6 that low risk areas like U.S.A and other western countries had alcohol and smoking contributing to 90% of the cases [41]. Another risk factor noted, was chewing betel nut and betel leaf. It had been very common in India. Nayar et al., conducted a study and noticed that this tradition would increase the chance of getting esophageal cancer by 3.16 times [100]. INFECTIOUS FACTORS Viral Agents: The risk of Human Papilloma Virus (HPV) infection was not clear, but it was believed that it was linked with the development of squamous cell carcinoma [39, 73]. Fungal Agents: There had been studies, which showed a potential association between fungi, most common candida albicans and esophageal cancer incidence [11]. Another factor taken in consideration by many studies was Helicobacter pylori [25, 148]. It has been noted that H. Pylori has actually a protective effect to adenocarcinoma but plays an opposite role, as a risk factor for squamous cell carcinoma. GENETIC FACTORS The researchers were questioning if genetic factors were linked with the development of esophageal cancer. There were not too many studies to prove the link. Akbari and his colleagues showed that familial and genetic factors play an important role as a risk factor for first-degree relatives of patients with esophageal cancer [5]. No particular genetic factors were recognized. 7 DIETARY FACTORS/ LOW SOCIO-ECONOMIC STATUS Nutrition plays a role as a risk factor. Although it is largely investigated, the role of diet is inconclusive. Populations that were at higher risk for squamous cell carcinoma were those with diets of corn, wheat, and millet, with minimal fruits, vegetables and animal products. The risk factors for adenocarcinoma of the esophagus are not well understood. Wu and co-workers did a study on the impact of dietary factors in developing esophageal and gastric cancer [149]. The study was done on 206 esophageal, 257 gastric and 366 distal gastric adenocarcinoma patients and 1,308 control subjects in Los Angeles. The conclusion of the study showed that high fiber intake is associated with a significant reduction in cancer risk [149]. Cook-Mozaffari and co-workers did a study in 1979 on esophageal cancer patients in Iran [31]. They wanted it to see if there was a strong association between a low intake of fruits and vegetables and the low-socio-economic class. The study showed that low-socioeconomic class, which had predominantly low protein diet, associated with low vegetables and fruits intake and excessive drinking of hot water increased the chances of developing esophageal cancer [31]. Although the exact cause is still unknown, another study showed the same conclusion: it was believed that poor nutrition and drinking beverages at high temperatures were associated with the onset of esophageal cancer [67,150]. The other risk factor appears to be obesity, especially for adenocarcinomas not so for squamous cell carcinomas [83]. Overweight, Barrett’s esophagus, gastroesophageal reflux disease (GERD) and dysplasia were known risk factors especially for adenocarcinoma. Kubo and Coorley did a review of observational studies, which included body mass index (BMI) and esophageal and cardia cancers [78]. It showed a direct relation between BMI and the risk of developing esophageal adenocarcinoma. An increase in BMI, increased the risk of cancer. The study showed that it was more relevant for men than women, for esophagus than cardia and no clear association with regards to China population. 8 The causative agent is not known, however, changes in life style, diets, deficient in Zn, Ca, etc. had all been shown to be contributing to esophageal cancer [122]. Selenium, dietary fiber, fruits and vegetables and antioxidants were seen as protective factors [13]. In review, it seems that a healthy lifestyle maintaining a good intake of proteins, fruits and vegetables with avoiding smoking, excess of alcohol consumption reduces the risk of esophageal carcinomas. 9 1.1.3 PATHOLOGY Histologically, esophageal cancer is classified into squamous cell carcinoma (SCC) and adenocarcinoma (AC) due to the variation in pathogenesis and cancer biology. This malignancy can occur within a) the gland cells known as adenocarcinoma, located usually in the distal third of the esophagus and gastroesophageal junction, or b) the squamous cells known as squamous cell carcinoma, which can be found anywhere along the esophagus, mostly upper two-thirds [139]. The squamous cell carcinoma has remained histologically the most common worldwide. However, adenocarcinoma of the esophagus has seen an increase in the proportions of epidemics in other Western countries and the United States. Both histologies have been documented to carry a poor prognosis [66]. Esophageal cancer is also classified according with the Japanese Research Society Committee. Based on the degree of differentiation there can be papillary/well differentiated, tubular/moderately differentiated and poorly differentiated tumors. This is related to the depth of invasion. If submucosal invasion exists, cancer is considered advanced and poorly differentiated [46]. 10 1.1.4 PRESENTATION Treatment of esophageal cancer is based on the assessment and diagnosis. The common signs are difficulty and/or painful in swallowing and weight loss. Many patients ignore the first signs of not being able to swallow. They change their food to puree or liquids, denying the severity of the problem. For the patient with advanced esophageal cancer, relief of dysphagia is the goal of therapy. Because of the tumor progressing rapidly, patients reach the stage when they cannot swallow liquids or their own saliva [37]. The severity of dysphagia can be quantified by using the scale proposed by Mellow and Pinkas [95] (Table 1.1.4.1). Table 1.1.4.1- Dysphagia Grading Grade 0 1 2 3 4 Symptom Able to eat normal diet Able to eat some solid food Able to eat semisolids only Able to swallow liquids only Unable to swallow anything, including saliva Because of the advanced stage at the initial presentation, it is recognized that an appropriate palliation for dysphagia, it is important for re-expanding the lumen of the esophagus and providing adequate nutrition support. The dysphagia grading can be used to quantify if a palliation method improves the symptom and if the approached method is effective for the patient (e.g. being able now to tolerate a liquid diet). Associated with dysphagia, is the finding of weight loss in about 42 to 46 percent of patients at diagnostic [111]. Pain in the back or retrosternal, occurs less often in about 20 percent of patients and suggests the existence of extensive disease in the surrounding areas or dilation of the proximal part of the esophagus with food [111]. Other problems may include the following: cough with eating or drinking, hoarseness, indigestion and heartburn, iron deficiency anemia, blood in the stool. Part of the assessment amongst the other symptoms can include drooling after swallowing, poor vocal quality after swallowing, head or neck adjustment to ease the swallowing [72]. 11 1.1.5 FACTORS AFFECTING PROGNOSIS One of the major concerns with esophageal cancer is the poor prognosis [116]. Of the symptoms experienced by esophageal carcinoma patients, dysphagia and weight loss are seen in more than 90% [19]. The onset of dysphagia is generally late, which prevents patients from seeking in depth diagnosis. The prognosis depends on the size of the tumor, the stage of cancer, the length of the tumor and the tumor pathology. Besides the extent of the disease and amount of weight loss, prognosis depends on the patient’s age and general condition. The patients are often elderly with severe comorbidities limiting the ideal treatment. Many patients will have locally advanced esophageal cancer where it is unresectable or it is considered metastatic [122]. In this case the diameter of the lumen of the esophagus is less than 13 mm and a significant weight loss will occur [45]. If the weight loss at presentation is more than 10-percent body mass this indicates a poor prognosis [45]. The understanding of esophageal adenocarcinoma is becoming far clearer in terms of biology. It was previously believed that it was systemic when it is diagnosed, but it is now clear that the esophageal cancer is similar with gastrointestinal cancers in that lymphatic metastasis arises earlier than systemic disease in most cases [101, 108, 123]. Since esophageal cancer is diagnosed late, it has a poor prognosis with a high local recurrence and metastasis [6]. Ilson in his study reinforced that patients with advanced esophageal cancer have poor prognosis due to the early systemic spread of the disease and a high incidence of failure with the local-regional treatment given [66]. Once the cancerous cells have reached the lymph nodes through the lymphatic system they can spread to any organ in the body. The common metastatic sites for esophageal cancer are: liver, lungs, bones and adrenal glands. The survival rate will therefore depend strongly on the stage of esophageal cancer, and it will decrease as the stage increases. 12 1.1.6 DIAGNOSTIC WORK-UP An accurate staging of the disease is essential, and several investigations are recommended. Physical Examination and History of the patient Barium Swallow Upper GI endoscopy and biopsy Chest/abdominal/Pelvic computed tomography (CT) scans Positron emission tomography (PET) evaluation preferred if no evidence of M1 disease (PET_CT preferred over PET scan) CBC and chemistry profile Endoscopic ultrasound (EUS) if no evidence of M1 disease, with FNA if indicated Bronchoscopy, if tumor is at or above carina with no evidence of M1 disease Laparoscopy (optional) if no evidence of M1 disease and tumor is at GE junction Biopsy confirmation of suspected metastatic disease HER-2 neu testing if metastatic disease is documented/suspected Diagnosis of esophageal cancer starts with a physical exam and history of the patient followed by chest-x-ray and barium swallow test. Importance has to be given what patient can swallow: liquids, semi-solids or solids. Questions to be asked which will be significant for a near or total esophagus obstruction include: if there is drooling after swallowing, if presence of a frothy sputum after swallowing, hoarse voice, regurgitation of the mucus. If the barium swallow test shows irregular filling defect or a stricture it can be a sign of presence of esophageal cancer and usually an endoscopy with multiple endoscopic biopsies is followed (Figure 1.1.6.1). This procedure verifies the diagnosis: the location, size and appearance of the cancer. 13 Figure 1.1.6.1- Advanced esophageal cancer: A, Near total obstruction; B, Barium swallow X-ray [51] For the early cancers, the tumor may appear as plaques, nodules or ulcers, but advanced cancer shows as strictures, mass ulcers, circumferential masses or very large ulcers. At this point histology of the tumor is confirmed. After diagnosis, staging is achieved by a combination of procedures. The initial recommended technique should include the computed tomography (CT) scans of chest, abdomen and pelvis with intravenous contrast. Recently positron emission tomography (PET) is used to evaluate the staging and presence of metastatic disease. Metastasis can be detected using integrated PET/CT scans. For T- and N stage endoscopic ultrasonography (EUS) is used that can estimate in 80- 90% of cases the depth of tumor invasion and also the involvement of lymph node metastasis (in 70-80% of cases) [143, 132]. Bronchoscopy is another procedure used for work-up for patients with an advanced esophageal tumor that is localized at or above the level of carina. The procedure rules out the possibility of an airway tumor invasion. Endoscopies with a biopsy, computerized tomography, endoscopic ultrasound examination, PET scan, all are part of the staging procedure and great importance in deciding the exact length of the tumor, how invasive the disease is and localization of the tumor. 14 1.1.7 ASSESMENT AND STAGING Esophageal cancer develops consecutively along a series of four stages. It is classified according to the 2010 American Joint Committee on Cancer (AJCC) (Table. 1.1.7.2 and 1.1.7.3) – tumor node metastasis (TNM) Classification system and the International Union Against Cancer (UICC) [109a]. In Canada the most common staging system used is the TNM classification. Furthermore the AJCC and UICC group the TNM data into stages. Both esophageal and gastric cancers are diagnosed and staged based on the results from several investigations. At stage 0 the cancerous cells are confined to the inner lining of the esophagus and are known as in situ (Figure 1.1.7.1). Figure 1.1.7.1- Esophageal Cancer Staging [133] Once the cancer is at Stage I, the malignant cells have penetrated the inner layer. Stage II is broken down into Stage IIA and Stage IIB. The cells have either entered the lymph nodes (Stage IIB), invaded the muscle layer (Stage IIA) and have grown through the outer layer of the esophagus. Most patients seek diagnosis by Stage II that is already late, 15 leaving the patient at risk for cancer spreading. By Stage III the cancer has invaded the lymph nodes and has began to spread to the trachea, the neighboring air canal organ [94]. Esophageal cancer is referred to as advanced esophageal cancer once it has reached Stage IV. During Stage IV, the cancer has spread to other parts of the body such as bones, liver or even brain, through a process known as metastasis. Metastasis is seen in over 50% of esophageal cancer patients at presentation [3]. 16 Table 1.1.7.2 - TNM 7th Edition of the AJCC Cancer Staging Manual: Esophagus and Esophagogastric Junction T classification Tis High-grade dysplasia T4a Resectable cancer invades adjacent structures such as pleura, pericardium, diaphragm Unresectable cancer invades adjacent structures such as aorta, vertebral body, trachea Regional lymph node- Any periesophageal lymph node from cervical nodes to celiac nodes No regional lymph node metastases 1 to 2 positive regional lymph nodes 3 to 6 positive regional lymph nodes C7 positive regional lymph nodes T4b N classification N0 N1 N2 N3 M classification M0 M1 Histopathologic No distant metastases Distant metastases Adenocarcinoma Squamous-cell carcinoma Histologic grade G1 G2 G3 G4 Cancer location Well differentiated Moderately differentiated Poorly differentiated Undifferentiated Upper thoracic Middle thoracic Lower thoracic Esophagogastric junction 20–25 cm from incisors 25 to 30 cm from incisors 30 to 40 cm from incisors Includes cancers whose epicenter is in the distal thoracic esophagus, esophagogastric junction, or within the proximal 5 cm of the stomach (cardia) that extends into the esophagogastric junction or distal thoracic esophagus (Siewert III). These stomach cancers are stage grouped similarly to adenocarcinoma of the esophagus 17 Table 1.1.7.3A- 7th Edition of the AJCC Cancer Staging Manual; Adenocarcinoma stage groupings STAGE 0 1A 1B 11A 11B 111A 111B 111C 1V T is(HGD) 1 1 2 2 3 1-2 1-2 43 4a 3 4a 4b Any Any N 0 0 0 0 0 0 1 2 1 0 2 1-2 Any N3 Any M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 G 1 1-2 3 1-2 3 Any Any Any Any Any Any Any Any Any Any Table 1.1.7.3B- 7th Edition of the AJCC Cancer Staging Manual; Squamous-cell carcinoma stage groupings STAGE 0 1A 1B 11A 11B 111A 111B 111C 1V T is(HGD) 1 1 2-3 2-3 2-3 2-3 1-2 1-2 3 4a 3 4a 4b Any Any N 0 0 0 0 0 0 0 1 2 1 0 2 1-2 Any N3 Any M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 18 G 1 1 2-3 1 1 2-3 2-3 Any Any Any Any Any Any Any Any Any LOCATION Any Any Any Lower Upper, Middle Lower Upper, Middle Any Any Any Any Any Any Any Any Any 1.2 TREATMENT OPTIONS FOR PALLIATION OF ADVANCED ESOPHAGEAL CANCER Dysphagia is the most common symptom for advanced esophageal cancer patients. Esophageal cancer symptoms are worrying and devastating. An effective palliation for dysphagia it is important for re-expanding the lumen of the esophagus or providing a source of nutrition at any point in the disease course. The stricture or obstruction occurs in more than 70% of patients with esophageal cancer. The normal diameter of esophagus lumen is 2.5cm in diameter and if a decrease to 1.3cm occurs, dysphagia appears affecting solid and regular food diet [45]. It implies the necessity of immediate attention with proper evaluation to define the cause and commence treatment. The treatment is used for the relief of symptoms, mostly dysphagia. The intent is palliative and remains a main focus because dysphagia impairs the patient’s nutrition and therefore the quality of life. Over the years many palliative options are available for palliation of esophageal cancer. A variety of palliative treatment methods have been promoted (Table 1.2.1). Table 1.2.1- Palliative Treatment Methods for Advanced Esophageal Cancer NON-ENDOSCOPIC TECHNIQUES Surgery Resection Excision Bypass Chemotherapy Radiation Therapy External Beam Radiation Therapy Brachytherapy ENDOSCOPIC TECHNIQUES Dilation Laser Therapy Stent Placement Photodynamic Therapy Argon Plasma Coagulation Chemical Injection Therapy Feeding Gastostromy COMBINED MODALITIES 19 Surgery is no longer an option for the patients with advanced esophageal cancer. Palliative radiotherapy with or without chemotherapy becomes the most common treatment modality. Other methods of palliation are endoscopic techniques. Not all patients can tolerate all the methods. The choice of palliation will depend upon three strong criteria: tumor characteristics, patient preference and patient performance status. When the treatment is mostly palliative, the aspect of the patient’s quality of life may be considered. The optimal approach is though controversial. A review of the various methods of palliation is beyond the scope of this thesis. A brief summary of the available methods and overall dysphagia improvement is presented in Table 1.2.2 and Table 1.2.3. 20 Table 1.2.2- Methods of Palliation and Median Survival Methods Brachy of therapy palliation By-pass Surgery EBRT Laser Chemo therapy Stent (Intubation) Author Mannell et al, 1991 [92] Sur 1994 Segalin et al 1989 [116] Kelsen et al, 1986 [77] Mannell et al, 1989 5months 4months 4months 2.5months Median Survival Sur, 1991 [127] 6-9 months Bown, 1991 [16] 4months 5-6months Madhusudan et al., 2009 2months Table 1.2.3- Comparison between treatment modalities for dysphagia relief [72] Treatment Modality Dysphagia relief Duration of relief Mortality Dilation 92% 1 week <1% Laser 80-90% 4-6 weeks 1%-2% Stent 95-100% Up to 20 weeks 0%-8% Photodynamic Therapy 85-90% 7-9 weeks 1%-2% Brachytherapy 50-80% 28 weeks No data Argon coagulation 80-85% 3-4 weeks NA Electrochemical 80-90% 4weeks NA NA – not applicable 21 1.3 OBJECTIVES AND AIMS The data in Table 1.2.3 show that brachytherapy is the best treatment option for the palliation of dysphagia. The objectives and aims of this thesis are to investigate the addition of chemotherapy to brachytherapy. In particular: 1. To evaluate the role of additional chemotherapy with brachytherapy in patients with advanced esophageal cancer with the following endpoints a) Dysphagia free survival b) Overall survival 2. To evaluate the incidence of complications in patients treated with brachytherapy alone or brachytherapy with additional chemotherapy 22 1.4 HYPOTHESES OF THE STUDY It is hypothesized that the combination of intra-luminal brachytherapy with chemotherapy will improve the survival of patients with esophageal cancer and that the patients will have a better control of dysphagia for a longer period of time. This will contribute to the current understanding of chemotherapy as additional treatment to brachytherapy for symptom management in the palliative setting. Alternative hypotheses There is an increased overall survival in esophageal cancer patients receiving High Dose Intraluminal Brachytherapy followed by Chemotherapy compared with those receiving High Dose Rate Intra-luminal Brachytherapy alone. There is an improved dysphagia free survival of esophageal cancer patients receiving High Dose Intraluminal Brachytherapy followed by Chemotherapy compared with those receiving High Dose Rate Intraluminal Brachytherapy alone. Null hypotheses There is no increment in the survival in esophageal cancer patients receiving High Dose Intraluminal Brachytherapy followed by Chemotherapy compared with those receiving High Dose Rate Intraluminal Brachytherapy alone. There is no improvement in the dysphagia free survival of esophageal cancer patients receiving High Dose Intraluminal Brachytherapy followed by Chemotherapy compared with those receiving High Dose Rate Intraluminal Brachytherapy alone. The addition of Chemotherapy to High Dose Rate Intraluminal Brachytherapy may not improve posttreatment complications. 23 1.5 REVIEW OF LITERATURE Many studies have shown that locally advanced esophageal cancer patients have a poor prognosis if treated only with a single treatment modality. The failure is due to early metastasis of the disease and the high incident of local recurrence. The need to improve dysphagia has made HDR brachytherapy an important treatment. The need to minimize the spread of esophageal cancer and to further improve dysphagia free survival and quality of life has led to the question if an additional chemotherapy treatment is an advantage. There are no studies done to report the effect of chemotherapy following HDRILBT in palliation of dysphagia and the difference in the overall survival rate for patients with esophageal cancer receiving either HDRILBT or HDRILBT with additional chemotherapy. 24 1.5.1 The role of brachytherapy in palliation of dysphagia Esophageal cancer often leads to death due to its severity. Although radical surgery has proven to be the most successful treatment of this severe disease, the majority of the patients are not operable at the time of diagnosis. In advanced esophageal carcinomas with or without distant metastases surgical palliation plays a minimal role mainly due to short life expectancy. Although there are some studies showing benefit from surgery palliation treatment, the procedure is rarely adopted. It may interfere with the opportunity for other alternatives such as definitive chemotherapy and radiation to have positive benefit. In esophageal cancer with advanced disease, nonsurgical modalities should be recommended in the majority of patients. A choice for palliation is provided by the external beam radiotherapy without or with concurrent chemotherapy [151]. Intraluminal brachytherapy has been reported as a method of palliation of advanced esophageal cancer and increase local control by many authors (Table 1.5.1.1). 25 Table1.5.1.1- High Dose Rate Brachytherapy – Palliative Results # Author 1 BHATT , 2012 2 # Pts. 21 Dose/fractio n 12Gy/1fract HDR Dysphagia relief 53% Survival HARVE 12 Y, 1993 12.5Gy/1fra ct HDR 4.5mo mean (11) 5.8mo mean 3-esophagitis 9-esophagitis 3 HOMS, 2002 149 6-20Gy/12fract HDR 51% 160days median 12% major complication 8%minor complication 4 HOMS 2006 95 12Gy/1fract HDR 74% 155 days median 12% major complication 8%minor complication 5 JAGER, 1992 37 15Gy/1fract HDR 5mo median 20%12mo 5-fistulae 1hematemesis 2-ulceration 6 KULH AVY, SUR LEVIN 1995 12 14 14 11 10Gy/1fract 12Gy/1fract 15Gy/1fract 18Gy/1fract HDR 5mo mean 5mo mean 6mo mean 8mo mean NR 2-failures 2-failures 1-stricture 3-stricture 1-fistula 8 LOW, 1992 12 15Gy/1fract 83% NR 33%esophag itis 17%pain 17%pyrexia 8%bleeding 9 SUR, 1991 9 12Gy/2fract HDR 3/9 pts-9mo 9mo 4-stricture 2-failure 3-esophgitis 1 SUR, 36 12Gy/2fract HDR NR 10%, 14%stricture, HDR 26 5mo median Complicatio ns NR 0 1996 68 68 16Gy/2fract 18Gy/2fract 1 1 SUR, 2002 112 120 16Gy/2fract 18Gy/3fract 1 2 1 3 SKOW 91 RONEK , 2004 WEI203 BOYIN, 1989 NR 20%fistula 25%stricture, 3%fistula 42%stricture, 11%fistula 207days median 243days median 11%stricture 10%fistula 22.5Gy/3fra ct HDR NR 8.2mo 11-fistula 65-pain 15-30Gy/24fract HDR NR 34.5%, 12mo 66% esophagitis 49.3% back pain 11.8% strictures 15Gy/2fract- HDR 13weeks NR 1-stricture 7 mean 1-fistula 15Gy/1fract6 #-Number; Pts.-Patients; Mo-Months; HDR-High Dose Rate; NR-Not Reported; GyGray; Fract-Fractions 1 4 WEE, 1994 HDR 1year 22%, 1year 35%, 1year 15 High dose rate Intraluminal Brachytherapy, in combination with chemotherapy and radiation or simply radiation, improves the outcome of the treatment because of the biological response. Due to the rapid dose fall off and the ability to deliver a high dose directly to the tumor site, brachytherapy is used for local boost [10]. Due to the limited time of treatment, ease of administration and better compliance by patients, high dose rate brachytherapy is most commonly preferred. Skowronek, Protrowski and Zweirzchowski conducted a study to analyse the outcomes from HDR brachytherapy of palliation for patients of advanced esophageal cancer [121]. 27 Most patients showed improvement in dysphagia. Both complete and partial remissions were seen for elderly patients. After the first month of treatment, dysphagia of a lower grade with longer survival was observed. An increase in pain was reported in sixty-five out of ninety-one patients during treatment and up to 3weeks later. In conclusion, there was a smaller size of tumour, a higher rate of Karnofsky Performance Status and clinical stage with a lower level were the important factors of prolonged survival. Harvey et al., used two different dose schedules for local advanced as well as metastatic esophageal carcinoma [59]. The medium dose rate Cesium-137 and high dose rate Iridium-192 was given to patients. In this study two types of brachytherapy were compared. The HDR-treated patients had a longer dysphagia relief (5.8 months) compare with MDR-treated patients (4months). Homs et al., studied the impact of HDR brachytherapy for palliation of the malignant dysphagia [61]. Dysphagia scores improved for HDR brachytherapy of 6 weeks at a median of 3 to 2 months but did improve the dysphagia in 49% patients. It was found that HDR brachytherapy was a moderate and effective treatment with a low occurrence of earlier complications. Homs et al., in another study, examined the use of a single dose of brachytherapy as a palliative treatment modality for the treatment of oesophageal carcinoma [62]. They found that a single dose of brachytherapy was not favourable for those patients who already underwent the chemotherapy treatment. A higher or fractionated dose may be a good options treatment for these patients. Other patients who did not receive already chemotherapy needed a single dose of brachytherapy. Jager et al., determined the efficacy of palliation by applying the single session of the intraluminal irradiation [71]. A dose of 15 Gray (Gy) prescribed at 1cm from the central axis was given to all patients. Fifty-one patients received Medium Dose Rate (MDR) treatment with Cesium 137 and thirty-seven patients received High Dose Rate (HDR) brachytherapy with Iridium 192. Dysphagia improved in fifty-five patients. There was a complete relief of swallowing for thirty-five out of fifty-five patients. A second treatment was applied to those patients who met with re-obstruction. Administration of intraluminal 28 irradiation was easier and safe, which formed a useful addition for therapeutic possibilities. Bhatt, Tirmazy and Sothi studied the symptoms of dysphagia, and reported the usage of HDRILBT at their centre for a number of years since 2006 [10]. Both survival and dysphagia were used as endpoints. The local database of radiotherapy was used to identify the patients and their details of treatment. A single fraction of 12 Gy was given to all patients in their study from a period of 2006 to 2010. The patients with adenocarcinoma were 62% and 38% patients were with squamous cell carcinoma. Patients with severe conditions of tumours received first line treatment of brachytherapy before chemotherapy. None of the patients showed the toxicity of acute esophagitis. This treatment was well tolerated and efficient and was considered the palliative treatment a choice for oesophageal cancer in the future. Sur et al., determined that fractionated brachytherapy was a significant modality for the process of palliation in the advanced esophageal cancer [129]. As compared with all available modalities, fractionated brachytherapy presented the best palliation. An optimal dose of brachytherapy ranged from 12 Gy to 18 Gy given in two fractions for a week. In a third study, Sur et al., worked on applications of fractionated HDR brachytherapy and found it as an effective way for palliation of advanced esophageal cancers [130]. They used two different dose fractions of 8 Gy x 2 and 6 Gy x 3, which gave similar results for survival, strictures, overall survival and equal effectiveness of palliation from dysphagia. Wee, Theobald and Chua found that the esophagus cancer was the most common in male population of Singapore [146]. Palliation treatment was given to all patients with advanced esophageal cancer. Patients were treated with a high dose of HDR brachytherapy of (Ir192) in a single or two fractions of 7.5 Gy per fraction. 63% of patients had an improvement in dysphagia lasting over 11 weeks. Sharma et al., included another factor of swallowing status in addition to overall survival and complication rate [119]. Patients included in the study were thirty-seven with no previous treatment and twenty-one with post-treatment recurrent tumours. The rate of 29 swallowing in 22 patients reduced and 24 patients had the same rate of swallowing, as it was pre-treatment. The untreated group had a low rate of complication as compared to the treated group of patients and higher median survival rate, but not significantly. The results indicated that use of HDRILBT was supported in achieving acceptable complications. Patients with an advanced stage of oesophageal cancer did not qualify for the surgery and constituted the poor prognosis. Applications of HDR brachytherapy for patients having the advanced esophagus cancer were analysed by Skowronek et al. [121]. For HDR brachytherapy, a dose of 22.5 Gy was given in three fractions at the exact sites of tumours. Results from the complete treatment were assessed after the 1st, 3rd and 6th month. Partial remission, total remission, and no remission were the important factors of study. In some cases, total remission was lasted for more than 6 months with good tolerance. However, complications were same as other authors reported in their studies. Gasper et al., worked on a prospective and multi-institutional study in order to find the tolerance, the feasibility of the external beam irradiation, in addition to esophageal brachytherapy and concurrent chemotherapy [52]. The results of this multi-institutional study were not optimistic as life-threatening toxicity occurred in 26% patients, which resulted into deaths of patients. The survival rate did not differ greatly from the application of external beam radiation, concurrent chemotherapy and esophagus brachytherapy as compared to only esophageal brachytherapy and chemotherapy. The concerning point of this study was the development of fistulas in a large number of cases. Therefore, an extreme need was required to combine these three techniques for patients with esophageal cancer. Another study, Gaspar et al., focused on the establishment of guidelines for brachytherapy for treatment of esophagus cancer [53]. For the development of recommendation in brachytherapy in the palliative and definitive treatment, some standards were established. Definitive treatment was based on the adenocarcinoma or squamous cell carcinoma =<10 cm length. As indicated in the earlier study of Gasper et al., the concurrent use of the external beam of radiation with chemotherapy and brachytherapy was more damaging as compared to alone treatment with brachytherapy 30 with chemotherapy, the concurrent use of three techniques was not used [52]. The use of external beam radiation was only plausible on the identification of a controversial 3 months of life expectancy. In such circumstances, the use of 25-40Gy as LDR (0.41Gy/hr.) and 15-20Gy in two to four fractions was set and considered beneficial. The use of a single dose brachytherapy and metal stent for palliation of the esophagus required the selection of the best option between two techniques. The work of Homs et al., was based on the comparison of stent placement and brachytherapy outcomes [64]. This study covered a large area of the Netherlands with the participation of nine hospitals. The total number of patients was 209 regrouped into two groups of patients for evaluation of two different techniques. Stent placement was applied for 108 patients and brachytherapy of a single dose (12 Gy) for 101 patients. The result of this study showed the fast improvement with stent in dysphagia as compared to brachytherapy. Stent placement produced many complications for the patient than brachytherapy such as late haemorrhage. Brachytherapy had a high score of quality of life than stent placement. The cost for brachytherapy as well as stent placement remained same. Instead of initial fast dysphagia improvement, the slow improvement from a single dose brachytherapy produced long-term relief for the patients. Homs et al., in other study on the same factors of single dose chemotherapy and stent placement, further explored the comparison between two techniques based on the quality of life related generically health specific and diseases [65]. In a similar statistics, the stent placement was carried in 108 patients and single dose brachytherapy (12 Gy) was carried in 101 patients. Change in health related quality of life, (HRQoL) were observed and analysed after treatment for both groups of patients. Similarly, the dysphagia development was fast in stent placement group as compared to the brachytherapy group of patients. On generic bases, the improvement in HRQoL was more favourable for brachytherapy as compared to stent placement. Deterioration in general HRQoL in the role and physical functioning became more common in stent placement group than brachytherapy group. However, stable improvements were seen in eating scales and dysphagia. Both groups showed the same 31 level of abdominal and chest pain. There was a need of generic HRQoL scales for future studies for palliative care of esophageal cancer in patients. The efficacy of brachytherapy depends on many treatment factors, brachytherapy fractionation, dose rate and dose, active length. The aim of the treatment is to relief dysphagia. The improvement in swallowing occurred in 51% of patients [62]. Tumour treated with MDR in Rowland and Pagliero study showed a 70% improvement for squamous cell carcinoma and 60% for adenocarcinoma [114]. MDR treatment was used in several studies: Harvey et al. and Jager et al., which reported the same, mean dysphagia relief of 5.1 months [59, 71]. High percentage of the dysphagia score between 80-95% was showed in Kaul et al, Low et al., study [79, 88]. The fractionation is important in quick relief of swallowing as shown in different studies. In 172 patients Sur et al. compared 18 Gy/3fractions with 16 Gy/2fractions and 12 Gy/2fractions, and concluded that the first fractionation reported better dysphagia free survival (38.9% vs. 25.4% vs. 11% at 12 months) [129]. The arm with 12 Gy over 2 fractions was stopped. Harvey et al. in his study compared two arms: 12 patients treated with HDR-ILRT 12.5 Gy/1fraction and 10 patients treated with MDR-ILRT 20 Gy/3fraction [59]. The first arm showed better improvement of dysphagia (5.1 vs. 4.5months). Kulhavy et al. reported a comparison of different doses delivered in a single fraction 10, 12, 15 and18 Gy [81]. The higher doses used for treatment, 15 Gy and 18 Gy, the better dysphagia relief. One of the complications reported by most of the authors is post treatment stricture ranging from 11.8-44%. Esophagitis is an early major complication and it was reported in Low et al. study in 33% of patients and Wei-Bo-Yin et al. study in 66% of patients [88,145]. Jager et al. reported 8% ulceration [71]. Comparing the different series, overall survival (mean or median) using intraluminal brachytherapy for advanced esophageal cancer ranges from 4.5 months to 9.9 months. 32 1.5.2 The role of chemotherapy in metastatic esophageal cancer - drugs used Esophageal cancer is often diagnosed late and has particularly a poor prognosis with high local recurrence and metastasis. The poor prognosis arises because most of the esophageal cancer patients are diagnosed late when the cancer has already spread [6]. In addition, not more than half of all the esophageal cancer patients are curative treatment candidates. In fact, even if the cure is attempted, esophageal cancer can still recur. In this regard, chemotherapy is very valuable in improving the chance in improving dysphagia and subsequently quality of life in patients with advanced esophageal cancer. Since 1970 chemotherapy was tested for esophageal carcinomas. Many single agents and combination regimens have been studied. First regimen adopted was the combination of 5-Fluorouracil plus Cisplatin. The two drugs served as a base for other studies then added a third or fourth agent to them. Just a few studies reported on AC of the esophagus. They indicated the same chemosensitivity for AC and SCC. Over the years the epidemiologic changes had occurred in the histological aspect of esophageal cancer, squamous cell carcinomas representing a minority of patients. The clinical trials conducted since 1980 showed that histologic subtype does not have a great role in survival rate and response rate in patients treated with different chemotherapy regimens. SINGLE OLD AGENTS Since 1990 single agents were used for chemotherapy treatment (Table 1.5.2.1). The agents were Bleomycin, Cisplatin, Methotrexate, Mitomycin, 5-Fluorouracil, Doxorubicin, and their response rate were low, varying between 10% and 20%, which approximates to a short duration less than six months. Another agent was Carboplatin but was infrequent used because appears to be less active. 33 Table 1.5.2.1- Old single chemotherapy agents OLD SINGLE AGENT (group) CELL TYPE HOW THEY WORK 5-Fluorouracil (Antimetabolites) SCC+ AC Irreversible inhibition of thymidylate synthase Methotrexate (Antimetabolites) SCC Cisplatin (Heavy metals) SCC+ AC Carboplatin (Heavy metals) SCC+ AC Mitomycin C (Anthracycline) SCC DOSE AUTHOR N RR % Ezdinli, E; 1980[43] 23 17 Ezdinli, E; 1980[43] 24 13 100 mg/m2 repeated every 3 weeks Bleiberg, H; 1997[14] 37 19 450 mg/m2 was given as a I-hour intravenous infusion Mannell and 11 Winters; 1998[92] 9 Whittington, 31 R; 1970[147] Bonadonna, 10 1972[15] 35 By bolus or continous infusion: 500 mg/M2 I.V. x 5 days q five weeks Inhibiting the 40 mg/M2 I. V. metabolism q one week of folic acid (in vivo) Crosslinking of DNA, which ultimately triggers apoptosis 15 mg/m2 x 20 2/week for 4 weeks SCC-Squamous Cell Carcinoma; AC-Adenocarcinoma; N-Number of patients; RRResponse Rate Bleomycin (Anthracycline) SCC 34 MAIN SIDE EFFECTS: 5-FLUOROURACIL Mouth and throat inflammation Low blood counts Severe allergic reactions Visual impairment Liver damage Fever Nosebleeds Weakness Confusion Headache Heart pain (angina) Diarrhea Stomach ulcers Dermatitis Discoloration of skin Alopecia Hand-foot syndrome, Stomatitis Neurotoxicities Cardiotoxicities Nausea and vomiting Diarrhea Alopecia METHOTREXATE Ulcerative stomatitis Low white blood cell count Nausea Abdominal pain Fatigue Fever Dizziness Acute pneumonitis and rarely pulmonary fibrosis CISPLATIN, CARBOPLATIN Nephrotoxicity Neurotoxicity Nausea, vomiting Ototoxicity Electrolyte disturbance Myelotoxicity Hemolytic Anemia 35 MITOMYCIN C Low blood counts (most common and severe) Rashes Hair loss Injection site inflammation Kidney damage Lung damage Fever Nausea Vomiting The response rate range varies for each agent, 19% has been observed for patients receiving Cisplatin [14]; 50% for Bleomycin [26]; 35% for patients receiving Mitomycin C [147] In a study, Ezdinli et al., 72 patients received randomly Adriamycin (ADR) 60 mg/m2 for three weeks intravenously or Methotrexate (MTX) for one week or 5-Fluorouracil (5-FU) over five weeks period [43]. The response rate for 72 patients remained as 5% for ADR, 13% for MTX and 17% for 5-FU. No complete response was observed. Patients were not benefited from ADR treatment for the advanced squamous cells carcinoma of the esophagus. Mannell and Winters worked on the Cisplatin’s role for squamous cell cancer of esophagus and found that substantial activity of Cisplatin reduced the benefits because of significant toxicity [92]. Carboplatin was used to keep and continue the antitumor activities and decrease the toxicity of Cisplatin. Carboplatin was given to eleven patients and found that it tolerated well in patients and showed reduced toxicity. It was a good alternative to Cisplatin. 36 SINGLE NEW AGENTS Table 1.5.2.2- New single chemotherapy agents NEW SINGLE AGENT (group) Paclitaxel (Taxane) -24 hour infusion TYPE HOW THEY WORK DOSE AUTHOR N R R SCC+ AC Stabilizing microtubules, interferes with the normal breakdown of microtubules during cell division 250mg/m2 repeated every 21 days (Q3w) Ajani, J; 1994[4] 50 32 80 mg/m2 weekly over a 1-h infusion Ilson, D; 2007[66] 10 2 15 70mg/m2 i.v., over 1–2 h, every 21 days(Q3w) Muro, K; 2004[98] 50 20 3 mg/m2 as a continuous infusion over 48 hours followed by 3 mg/m2 iv weekly for 4 weeks and then by monthly Bezwoda, WR; 1984[8] 52 27 25mg/m2 short i.v. infusion weekly Conroy, T; 1996[33] 46 15 Kulke, M; 2006[82] Ezdinli, 1980[43] 29 7 20 5 Weekly short infusion Docetaxel (Taxane) SCC+ AC Vindesine (Alkaloids) SCC Vinorelbine (Alkaloids) SCC Inhibiting mitosis through interaction with tubulin AC Doxorubicine (Anthracycline) SCC Interposing DNA strands Triggers DNA cleavage by topoisomerae II resulting in 37 mechanisms that lead to cell death Generating free-radicals cause cell and DNA damage. Etoposide (Topoisomerase inhibitor I) SCC AC Irinotecan (Topoisomerase inhibitor II) AC Forming a ternary complex with DNA and the topoisomerase II enzyme prevents religation of the DNA strands, causing DNA strands to break prevents DNA from unwinding by inhibition of topoisomerase I 200 mg/m2 on 3 Harstrick A; 26 consecutive 1992[57] days every 3 weeks (Q3w) 19 Weekly 125 mg/m2 15 Enzinger P; 2000[42] 38 1250 mg/m2 Sandler, 21 4 over 30–60 AB; minutes on days 2000[114] 1, 8, and 15 followed by 1 week of rest SCC-Squamous Cell Carcinoma; AC-Adenocarcinoma; N-Number of patients; RRResponse Rate; Gemcitabine (Deoxycytidine nucleoside analog) SCC AC Inhibit processes required for DNA synthesis 38 MAIN SIDE EFFECTS: TAXANES Life-threatening allergic reactions Low blood pressure Heart damage (slowing of the heart rate) Low blood counts Nerve damage Nausea Vomiting Diarrhea Unusual infections Edema (swelling) VINORELBINE Bone marrow damage Nerve damage Headache Face pain Nausea, vomiting, diarrhea, constipation Liver damage Inflammation of the mouth Fever Hair loss Rashes Muscle damage ETOPOSIDE Low blood pressure Hair loss Pain and or burning at the IV site Constipation or diarrhea Metallic food taste Bone marrow suppression, leading to: Decreased white blood cell counts (leading to increased susceptibility to infections) Low red blood cell counts (anemia) Low platelet counts (leading to easy bruising and bleeding) IRINOTECAN Low blood counts Nausea, vomiting, diarrhea, constipation, abdominal pain Liver damage Blood clots Low blood pressure Breathing problems Inflammation of the mouth Lightheadedness 39 Sleepiness Insomnia Fever Headache Hair loss Rashes GEMCITABINE Flu-like symptoms such as muscle pain, fever, headache, chills, and fatigue Fever (within 6–12 hours of first dose) Fatigue Nausea (mild) Vomiting Poor appetite Skin rash Allergic reaction Diarrhea Weakness Hair loss Mouth sores Difficulty sleeping Shortness of breath The main new agents confirmed for advanced esophageal cancer include: Taxanes (Paclitaxel and Docetaxel), Vinorelbine, Irinotecan, Oral 5-FU prodrugs, Capecitabine (Table 1.5.2.2). The response rate range varied for each agent, 26-34% for the patients treated with Capecitabine [89];15-20% for Vindesine and Vinorelbine [76]; 15-32% in the patients treated with Paclitaxel [4,66]; 20-25% response rate in case of Docetaxel treatment [42, 98]; 0-19% response rate for patients with Etoposide and 15% for Irinotecan [90]. Ilson et al., applied the weekly Paclitaxel (Taxol) for one hundred and two patients with advanced oesophageal cancer and found limited activity of Taxol [66]. One cycle was 1 week of treatment with Paclitaxel 80mg/m2 weekly over a 1-hour infusion. They showed 172 days being the median duration of response. They concluded that Taxol might be a good option for those patients who could not tolerate the combined chemotherapy. 40 In another work of Muro et al., the author evaluated the toxicity and activity of Docetaxel for the patient with metastatic esophageal cancer [98]. Dose of Docetaxel used was 70 mg/m2 given intravenously for 1 to 2 hours for 21 days. Total of 52 patients were enrolled and 3 of them did not take Docetaxel because their conditions worsened very early of treatment. Ten patients showed a partial response with a grade 3 or 4 neutropenia, and febrile neutropenia. Survival time at median level was 8.1 months. Although, Docetaxel as a single agent produced good results but the complication of neutropenia was complex and needed a careful management. From the study of Heath et al., it was determined that Docetaxel as a single agent did not provide improvement in chemotherapy efficacy [60]. No complete response was seen and the median survival time remained as 3.4 months. In an open study Bezwoda et al., applied the Vindesine at the dose of 3 mg/m2 on 52 patients for advanced esophageal cancer [8]. The treatment was given for 4 weeks followed by monthly maintenance therapy with the same dose. Only 27% patients responded positively with prolong survival. It was found that Vindesine had a definite impact but with limited influence against oesophageal cancer. Kulke et al., found the same conclusion in a phase II study regarding Vinorelbine used as a single agent; twentynine patients treated or untreated with the metastatic gastroesophageal adenocarcinoma disease were entered and they received a weekly dose of 25 mg/m2 Vinorelbine [82]. High overall response rate with respect to Capecitabine was shown in the study done by Lee et al., in a range of 57.8% [84]. Bonadonna et al. studied the application of intravenous Bleomycin (BLM) from phase I and phase II in 176 patients [15]. Different doses based on varying schedule were employed. The main side effect seen with BLM was pulmonary toxicities. The most important and less toxic regimen was with 15 mg/m2 x 2/week for 4 weeks. A lower dose of BLM resulted into a lesser incident of the lung toxicity. Enzinger et al., reported findings on 46 patients who were previously untreated with metastatic esophago-gastric adenocarcinoma [42]. An intravenous dose of the Irinotecan was applied for 90 minutes and continued for 4 consecutive weeks. After 4 weeks of 41 treatment patients were given rest for two weeks. The response rate was 14% as only one complete and five partial responses were seen. It was found that Irinotecan as a single active agent had moderate toxicity at the schedule. They also suggested that a single agent used three times within a week was more preferred for the same population. In later work of Burkart et al. it was found that Irinotecan as a single agent had moderate activity for esophageal cancer in a Cisplatin-refractory [20]. COMBINATION OF CHEMOTHERAPY DRUGS Several single agents demonstrated modest activity as anti-tumour agents. However, combined agents also provided effective results in several studies for the solid tumours of oesophageal cancer. Most used combinations for adenocarcinoma of the esophagus are: Cisplatin and Fluorouracil (CF) or Cisplatin and Capecitabine (CX), Epirubicin, Cisplatin and Fluorouracil (ECF), Epirubicin, Oxaliplatin and Capecitabine (EOX). For squamous cell carcinoma of the esophagus the most common combinations are: Cisplatin and Fluorouracil (CF) or Cisplatin and Capecitabine (CX). The other different combinations may include Taxol, Vinorelbine, Irinotecan. Cisplatin/5-fluorouracil (5-FU) Cisplatin and 5-FU are two drugs that are widely used for esophageal cancer patients, either as a combination of the two of them or one of them as a backbone with other agents (Taxane or Irinotecan). Positive responses to Cisplatin and 5-FU were seen for locaregional disease. For advanced metastatic or unreseactable disease, most studies reported low response rates between 35% and 40% [14]. Cisplatin (CDDP) 100 mg/m2 was combined with the 5-Fluorouracil and applied for 1 to 5 days at a dose of 1000 mg/m2 (Arm A) or it was given alone CDDP (Arm B). There was a repetition of cycles for 3 weeks. Out of 92 patients, 88 were found eligible. The response rate was found to be 35% in Arms A and in Arm B was 19%. The survival duration at a medium level was 33 42 weeks and 28 weeks for A and B arm respectively. In Arm A, the toxicities of haematological and non- haematological were found severe. In Arm A, about 16% deaths related with treatment were observed, and no death was found in Arm B. Hence, no standard chemotherapy was suggested and recommended for the patients with esophageal cancer [14]. Iizuka et al., designed a study for the evaluation of the 5-Fluorouracil (days 1-5) and Cisplatin (day1) effectiveness for thirty-nine patients with advanced squamous cell oesophageal carcinoma [70]. The patients who had positive response to the chemo regime showed a survival rate of 9.5 months compared with 5.6months for patients who did not responded to treatment. They found that combination of the drugs used, had reasonable effects and may be used for the postoperative chemotherapy as demonstrated mild side effects. Cisplatin and 5-FU chemotherapy regimen was considered standard therapy when given pre-operative for esophageal and gastro-esophageal junction adenocarcinoma. For squamous cell carcinoma and adenocarcinoma of esophagus, the combined chemotherapy was given concurrent with radiation therapy. No surgery was offered. Lately, the two drugs were combined with a third agent, usually epirubicin on ECF regimen or docetaxel in DCF regimen. Cisplatin/Paclitaxel Ilson et al., treated 38 patients with advanced esophageal cancer with Cisplatin (CDDP) 75 mg/m2 iv d2 in combination with Paclitaxel (Taxol) 200 mg/m2 civi over 24hrs d1 Q3w [66]. Overall dysphagia relief was 80 percent with a complete dysphagia relief of 72 percent. Polee et al., applied the combination of paclitaxel and Cisplatin for patients at a dose of 180 mg/m2 Paclitaxel and Cisplatin 60 mg/m2 every two weeks for three times. After 43 receiving this dosage patients were referred to surgery [106]. Nearly 71% patients suffered from haematological toxicity. The overall response rate was measured 59% and pathological examination resulted into a tumour free margin for 38 patients. The treatment was well tolerated with a median overall survival (OS) of 20 months. Van der Gaast et al., (1056) worked on Paclitaxel advantages given either as a single agent or combined with Cisplatin. Because of a brief period of neutropenia, a high dose for a shorter period was possible [137]. An increase of dose up to 200 mg/m2 of Paclitaxel combined with Cisplatin at a dose of 60 mg/m2 became possible. There was not toxicity related with haematological dose-limiting. A higher dose of paclitaxel delayed the treatment percentage because granulocytopenia could not increase substantially. This suggested that treatment was safe as the granulocyte count was >0.75 x109 I-j. Carboplatin/Paclitaxel Paclitaxel in combination with Carboplatin is a regimen that produces complete disease regression in about 25% of the patient with advanced esophageal cancer. In a phase I study, Polee et al., treated the patients with Paclitaxel at a dose of 100 mg/m2 with a combination of Carboplatin to follow on specific days such as “1, 8, 15, 29, 36 and 43” [107]. The study showed a recommended dose level for Carboplatin for other studies and trials. About 77% patients suffered from neutropenia of grade 3 and grade 4. There was shown well tolerance of treatment in all patients. The acceptable level of toxicity was achieved. Other toxicities were either mild or absent. The response rate observed during this Phase I study was noted as 54% that seemed to be high as most patients were with liver metastasis. This study concluded that Carboplatin combined with Paclitaxel could be useful if patients were untreated advanced oesophageal cancer. 44 Cisplatin/Irinotecan A phase II study done by Ilson and colleagues reported results about a chemotherapy regimen of Cisplatin (CDDP) 30 mg/m2 iv with Irinotecan (Camptosar, CPT-11) 65 mg/m2 iv given weekly on day 1,8,15, 22 followed by 2 weeks of rest in advanced metastatic esophageal cancer. Complete dysphagia relief was seen in 14 of 20 patients (70%) [66]. Cisplatin/Bleomycin (DB) Coonley et al., studied the effects of two combined drugs such as Bleomycin (DB) and Cisplatin [32]. Patients having locoregional disease (LRD), the Bleomycin was given before radiation therapy or surgery. In the case of extensive disease (ED), about 27 patients were primary treated with DB. The response rate was observed as 14% in LRD and 17% in extensive disease (ED). Minimum follow-up for the LRD group of patients was continued for 42 months and resulted that 10% patients remained alive with no disease. On the other hand, the follow-up for the ED group continued for 6 months. Other phase II studies that combine two chemotherapy agents and reported dysphagia relief are shown in the table 1.5.2.3. Table 1.5.2.3- Combination of two chemotherapy agents Author N Treatment Overall dysphagia relief (%) 89 Spiridon 27 Etoposide + idis et al cisplatin [126] Tebbutt 12 5-FU + 64 et al 9 mitomycin [131] N-Number of Patients; NS-Not Significant 45 Complete dysphagia relief (%) 89 Duration of relief (months) 93 Survival (months) NS NS 5.3 9.8 Cisplatin/5-FU/Paclitaxel Petrasch et al., found that Paclitaxel as a single agent was effective for both types of adenocarcinoma and squamous cell carcinoma of the esophagus. In a setting, patients were treated by Paclitaxel at dose of 90 mg/m2 for 3 hours and followed by Cisplatin 50 mg/m2 [103]. This treatment was repeated each 14 days. The remission rate was found as 40% with complete responses. Only 10% patients suffered from neutropenia of grade 3 and no grade 4 neutropenia was observed. Patients with a poor prognosis showed improvement after Cisplatin and Paclitaxel treatment given for 14 days with an accepted level of toxicity. Kok and associates studied the same regimen but different doses of Cisplatin and Paclitaxel. 52% of patients had objective response and grade 3 and 4 granulocytopenia was the main toxicity seen [80]. Epirubicin/Cisplatin/5-FU (ECF) vs. Epirubicin/Ciplatin/Capecitabine (ECX); Epirubicin/Oxaliplatin/Fluorouracil (EOF) vs. Epirubicin/Oxaliplatin/Capecitabine (EOX) Phase II and phase III studies were conducted with agents, which potentially can substitute Cisplatin and 5-FU. Cunningham and associates compared in two-by-two study design Epirubicin/Cisplatin/5-FU (ECF) vs. Epirubicin/Ciplatin/Capecitabine (ECX); Epirubicin/Oxaliplatin/Fluorouracil (EOF) vs. Epirubicin/Oxaliplatin/Capecitabine (EOX) for patients with advanced esophageal and gastric cancer [36]. Epirubicin + Cisplatin + Capecitabine (ECX) Epirubicin 50 mg/m2 iv bolus d1 q3w x 8 cycles Cisplatin (CDDP) 60 mg/m2 iv d1 q3w x 8 cycles Capecitabine (Xeloda) 625 mg/m2 po bid x 6 months Epirubicin + Oxaliplatin + 5-FU (EOF) Epirubicin 50 mg/m2iv bolus d1 q3w x 8 cycles Oxaliplatin (Eloxatin) 130 mg/m2 iv over 2 hours d1 q3w x 8 cycles 5-FU 200 mg/m2/d civi x 6 months Epirubicin + Oxaliplatin + Capecitabine (EOX) Epirubicin 50 mg/m2 iv bolus d1 q3w x 8 cycles Oxaliplatin (Eloxatin) 130 mg/m2 iv over 2 hours d1 q3w x 8 cycles Capecitabine (Xeloda) 625 mg/m2 po bid x 6 months 46 Cisplatin + 5-FU + Epirubicin (ECF) Epirubicin 50 mg/m2 iv bolus d1 q3w x 8 cycles Cisplatin (CDDP) 60 mg/m2 iv d1 q3w x 8 cycles 5-FU 200 mg/m2/d civi for 6 months All regimes showed comparable results, the response rate being 31% to 48% across treatment arms. Median survival times for ECF, ECX, EOF, and EOX were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively. Findlay et al., in a study found that ECF showed a high level anti-tumour activity with a low level toxicity [48]. A recent trial done by Ross and associates involved almost 600 patients with advanced esophageal cancer with histology, squamous cell carcinoma and adenocarcinoma. The study compared Epirubicin, Cisplatin and 5-FU (ECF) regimen to Mitomicyn, Cisplatin, 5-FU [112]. Both regimens had similar the response rate and median survival (42%, 9.4 months for ECF compared with 44%, 8.7 months for Mitomycin regimen. Cisplatin/5-FU/Adriamycin Gisselbrecht et al. used the combination of Adriamycin, Cisplatin, and 5-Fluorouracil (FAP) with hydration and mannitol-induced diuresis [55]. This combined course of medicine was given for four weeks for all 21 patients. The results from this study reported that seven out of 21 patients (33%) showed objective response, two with complete responses and five responses remained partial. All patients had metastasis before the treatment. The survival at the median level was found to be 8 months for 21 patients. There was no sever nephrotoxicity or myelosuppression observed as side effects. 5-FU/Cisplatin/Folinic acid/Etoposide In order to test the efficacy and toxicity of four combined drugs such as 5-FU, Cisplatin, Folinic acid and Etoposide, Polee et al., conducted a phase II study for patients with oesophagus carcinoma cancer [107]. A dose of combined drugs was given 6 times per day for 4 weeks. Evaluation of response from patients was taken after every two courses. Patients suffered from haematological toxicities such as leukocytopenia 16%, 47 thrombocytopenia in 7% patients, and non-haematological toxicity was seen as vomiting, diarrhoea and mucositis in patients. The response rate was observed as 34% (30% partial and 4% complete). The median time for progression was as seven months for 17 patients without any additional treatment. The median survival time was noted as 9.5 months, and the survival rate of one year. It was concluded that combination of these four drugs was an active and safe treatment for patients with advanced squamous cell carcinoma. Mostly phase II clinical trials have a higher response rate for combination of two or three chemotherapy agents in advanced esophageal cancer compare with single agent chemotherapy. Despite higher response rate, survival rate stays unclear. Non- cisplatin/5-FU based combinations Paclitaxel/Etoposide/Cisplatin Combination of three drugs such as Paclitaxel (T), Etoposide (E) and Cisplatin (P) also known as (TEP) were active alone as well as combined for the gastro- esophageal carcinoma. All 25 patients, eighteen with local disease and seven with liver metastases at presentation received the drug TPE. All patients had experienced neutropenia and grade 3anaemia. Out of 25 patients, 22 were evaluable, and 3 patients showed complete response while 19 presented partial response. The study showed a positive outcome with twenty-three patients alive. It was also suggested that the introduction of 5-Fluorouracil could be beneficial due to its role for the same disease [91]. Cisplatin/Vindesine/Mitoguazone (DVM) Kelsen et al., studied a combination of three drugs such as Cisplatin, Vindesine and Mitoguazone (DVM) [77]. DVM produced the toxic effects of leucopoenia but no evidence of pulmonary toxicity was observed. The level of toxicity was acceptable for the esophagus cancer cells. Even though, there was a reduction in the pulmonary damaging 48 risks, but the substitution of mitoguazone for bleomycin could not increase the capability for dose limiting toxicity for myelosuppression. Docetaxel/Irinotecan Burtness et al., enrolled in his study 29 patients with advanced esophagogastric cancer and no previous treatment and 15 patients with chemotherapy-exposed [21]. A combination of Irinotecan 50mg/m2 and Docetaxel 35 mg/m2 was given on day 1 and day 8 of a 21-day schedule for the. Patients with no previous treatment had a partial response of 26.9% and one a complete response. Just two chemotherapy-exposed patients had a partial response. The study showed that a weekly schedule with a safety regimen Docetaxel-Irinotecan was established for patients who did not receive prior chemotherapy. Epirubicin/Cisplatin/Oral UFT/Leucovin In spite of benefit of the treatment of 5-FU with protracted venous infusion (PVI), Choi et al., applied the new regimen with Leucovorin and oral UFT (Tegafur, a prodrug that is converted by the liver to 5-FU, and Uracil, a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for Fluorouracil catabolism) in order to improve the complication related with catheter and convenience [27]. The schedule was a combination of: Epirubicin, Cisplatin, oral UFT and Leucovin. The response rate was highly optimal 45.9% and one of the patients showed a complete response. There was 13 months median survival. Adenocarcinoma was observed in four patients and the response rate went up to 75%. The most important toxicity found was myelosuppression while other toxicities were at an acceptable level. Therefore, the combination of Epirubicin, Cisplatin, UFT and Leucovin was found an alternative of ECF for patients of advanced oesophageal cancer. Chau et al., conducted a study on a large population; 2110 patients with adenocarcinoma of esophagus, gastro-esophageal junction (GEJ) and stomach were enrolled in four 49 randomized control trials [28]. The regimes assessed were Fluoropyrimidine +/platinum-based chemotherapy: 1) ECF or FAMTX (Fluorouracil, Doxorubicin, Methotrexate) (Waters et al., 1999) (Webb A et al., 1997); 2) ECF or MCF (Mitomicyn, Cisplatin, 5-FU) (Ross et al., 2002); 3) 5-FU or 5-FU plus Mitomycin (Tebbutt NC et al., 2002); 4) ECF, ECX, EOF and EOX (Cunningham D et al., 2008) The median overall survival was 9.5 months in esopageal, 9.3 months in GEJ and 8.7 months in patients with gastric cancer. There was no difference at a large level on the multivariate analysis for response rate, overall survival and toxic effects for patients with esophagus and gastric cancers. The next chemotherapy regimens demonstrated to be a small efficacy for a long-term management of advanced esophageal cancer. Dinwoodie et al., conducted their study on a combination of Vindesine, Bleomycin and Cisplatin [40]. The trial was conducted for 27 patients and 7 patients showed partial response within early therapy. Out of 27 patients, 13 patients received greater than two cycles. Out of thirteen patients, five patients finished the intended 5 cycles of the treatment. They did not show any progress while they received more three cycles. A major side effect was seen as the granulocytopenia in 52% patients. Bleomycin lung toxicity was also observed in 2 patients. It was concluded that the same treatment could not be continued for more than 3 cycles for patients with advanced oesophageal cancer. De Besi et al., used tri-combination of drugs such as Cisplatin, Bleomycin and Methotrexate for the treatment of esophageal cancer from 1981 to 1982 [38]. Thirty-one patients with local advanced oesophageal carcinoma were applied the combination of three drugs as mentioned above. Out of 31 patients 16 showed improvement. However, only 8 patients (26%) had given the major responses. The responses were obtained within the initial two courses. The most prominent side effects of mild myelosuppression and gastrointestinal toxicity were reported. 50 More than 50% of patients with esophageal cancer are unresectable at presentation. Chemotherapy is a palliative treatment, which alone shows to improve dysphagia and quality of life in 60 to 80% of patients [66, 103]. THE ROLE OF CISPLATIN/5-FLUOROURACIL Cisplatin and 5-FU are two drugs that were widely used either alone or as a combination chemotherapy regime or one of them as a backbone with other agents. Lately, the two drugs are combined with a third agent, usually Epirubicin on ECF regimen or Docetaxel in DCF regimen. In the literature there are several studies done to evaluate Cisplatin as single agent chemotherapy. The majority of them were looking only at squamous cell carcinoma of esophageal cancer. With an increased in adenocarcinoma incidence more trials are evaluating both types of histology. Cisplatin and 5-FU chemotherapy regimen became the standard therapy and the most effective regimen for advanced metastatic esophageal cancer in squamous cell carcinoma and adenocarcinoma because of their drug interaction [120]. There are several studies that are evaluating the regime, Cisplatin and 5-FU, in different doses. One study done by Bleiberg et al. used Cisplatin 100mg/m2 on day 1 and 5-FU 1,000mg/m2/d by continuous infusion. The results showed that the combination of Cisplatin with 5-Fluorouracil had a better response rate (35%) than Cisplatin alone. The survival rate was similar. Comparable overall response rate was seen in other studies done by Hayashi et al. (33.3%) or Caroli-Bosc et al. (33%) [56, 23]. Webb and colleagues (73) in a prospective study evaluated the survival rate for the ECF regime [144]. The trial compared ECF with a regimen: 5-Fluorouracil, Doxorubicin, Methotrexate (FAMTX). 256 eligible patients were entered in the study. The results concluded that ECF survival rate of 8.9 months is more superior to 5.7 months for FAMTX. 51 2.0. PATIENTS AND METHODS The study is a retrospective study of a prospective non-randomized data base of 132 patients. Patients diagnosed with stage III/IV advanced esophageal cancer and metastatic disease were treated with High Dose Rate Intraluminal Brachytherapy alone or with additional chemotherapy at the Juravinski Cancer Centre (JCC), Hamilton Health Sciences Corporation. All patients were treated initially with palliative HDR Intraluminal Brachytherapy (HDRILBT). Two or three weeks after the completion of HDRILBT, chemotherapy was given to selected patients. Patients suitable for the additional chemotherapy received Epirubicin, Cisplatin and 5-Fluorouracil (ECF) regimen prescribed by the medical oncologist. All patients included in the study had total or near total dysphagia at presentation. None of patients received adjuvant external radiation therapy. The primary end point was dysphagia free survival. The secondary end point was overall survival. Brachytherapy was intended to treat disease in the luminal aspect of the esophagus to maintain swallowing while chemotherapy was meant to treat systemic disease. All patients were seen in a GI Multidisciplinary Clinic and reviewed by a Thoracic Surgeon, Radiation Oncologist, Medical Oncologist, Radiologist, and Pathologist together after all investigations were completed. 52 Dysphagia scoring was done on a 5 point scoring system: 0, no dysphagia; 1, dysphagia for solids; 2, dysphagia for semisolids; 3, dysphagia for liquids; and 4, total dysphagia. An improvement of dysphagia was recorded if there was an improvement by at least one grade. The EORTC-QLQ was used for recording dysphagia (Table 2.1). Table 2.1- EORTC-QLQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire QUESTION: Not at all A little Quite a bit 1. Could you eat solid food? 1 2 3 Very much 4 2. Could you eat liquidized or soft food? 3. Could you drink liquids? 1 2 3 4 1 2 3 4 4. Have you had trouble with swallowing your saliva? 1 2 3 4 Dysphagia-free survival was defined based on the 4 question scores from the table above. The dysphagia scoring algorithm is illustrated in Table 2.2. ~~ If the sum of the first two questions was adding up to 6, 7, 8 dysphagia score was classified as “0” (no dysphagia), ~~ If the sum of the first 2 questions was equal to 5 dysphagia score was “1” (dysphagia to solids), ~~ If the sum of the first 2 questions was equal to 4 dysphagia score was “2” (dysphagia to semisolids) ~~ If the sum of the first 2 questions was equal to 2 or 3 and the 3rd question was 3 or less dysphagia score was classified as a “3” (dysphagia to liquids) ~~ If the sum of the first 3 questions was equal to 3 and the 4th question was 3 or 4 dysphagia score was classified as “4” (total dysphagia) 53 Table 2.2- Dysphagia algorithm Q1 score Q2 score 4 3 3 2 1 2 1 1 1 1 1 1 1 4 4 3 3 4 2 3 2 2 1 1 1 1 SUM of Q1+Q2 scores 8 7 6 5 5 4 4 3 3 2 2 2 2 54 Q3 score Q4 score 3 2 3 2 1 1 3 4 DYSPHAGIA score 0 0 0 1 1 2 2 3 3 3 3 4 4 HIGH DOSE RATE BRACHYTHERAPY Brachytherapy is a form of radiation treatment where radioactive sources are placed in or near the treatment site. High dose rate brachytherapy is brachytherapy delivered with a dose rate of >12 Gy/hr. Typically, the radioactive source used is Iridium-192 (Ir192), with an activity of up to 10 Ci. At JCC the radiation is delivered using a VariSource HDR Remote Afterloader Unit (Figure 2.8) using a single source with a diameter of 0.34 mm and length of 5 mm. Figure 2.8- Remote Afterloader Brachytherapy Unit Figure 2.9- Barium swallow examination of an complete tumor obstracted esophagus 55 Figure 2.10- Localization of Intra-oral tube/Catheter in situ The treatment was performed as an outpatient procedure under conscious sedation. A preHDRILBT treatment barium swallow examination was carried out for each patient to fluoroscopically visualize the area where the tumor obstructed the esophagus (Figure 2.9). After premedication, the radiation oncologist performed an endoscopy, which is the most convenient, safe assessment of the tumor. The procedure was assisted using fluoroscopy. Either a 7mm esophageal applicator, which contains the 1.7mm esophageal catheter or the catheter alone, was temporally placed intraluminal in the esophagus with the aid of a flexible tip wire (Figure 2.10). After the placement of the applicator with a marker wire inside (Figure 2.11), an X-ray image was taken to define the tumor length. 56 Figure 2.11- Marker wire used to measure the tumor length The active length (tumor volume) of the treatment was visualized/identified and documented by gastro-esophagoscope and then marked fluoroscopically. The marker wire was removed from the catheter and the catheter was attached to the high dose rate brachytherapy afterloader. The dose was delivered to the entire tumor length plus an additional 2cm margin in the craniocaudal direction (Figure 2.12). Figure 2.12- Diagram showing definition of the target volume 57 For all patients the dose was prescribed at 1cm from the central axis. Based on the dose and tumor length a treatment plan was generated using Brachyvision planning software. The Treatment plan showed a high conformity of isodose lines to the tumor volume with good sparing of normal tissues from vicinity (Figure 2.13). The treatment prescription was a dose of 18 Gy divided in 3 fractions with 6 Gy per fraction, given over two week’s period. All patients finished all 3 fractions. Figure 2.13- Treatment Plan Distribution. 58 CHEMOTHERAPY Chemotherapy was given after 2-3 weeks after completion of the last fraction of the HDRBT. The chemotherapy regime, ECF was given as a day patient and included: Epirubicin 50mg/m2 IV day 1(1 cycle) 3-weekly was given as an injection along with a drip of saline Cisplatin 60-100mg/m2 IV day 1(1cycle) 3-weekly - given as an infusion 5-Fluorouracil (5FU) infusion 750-1000mg/m2 day IV 1-5) every 28 days for 3 cycles Dose calculation of all chemotherapy drugs was based on body surface area. The body surface area was calculated by using the actual body weight. Laboratory investigation was done for each patient before the treatment started a. Complete blood work b. Coagulation profile c. Base line renal function serum creatinine, electrolyte, urine routine. For chemotherapy to maintain the same weight during the course of treatment was very important. In case of a weight change, around 10% or more, treatment doses had to be recalculated. TIMING OF BRACHYTHERAPY with CHEMOTHERAPY Chemotherapy when given in addition to brachytherapy the sequencing was important. 59 FOLLOW-UP All patients were booked for a 6 weeks follow-up after the last HDR treatment. After that, follow-up was booked with the radiation oncologist every 3 months up to 24 months. Even though the patients were booked to see the doctor every 3 months they were asked to call any time if swallowing problems occurred: difficulty swallowing or pain during swallowing. Before each appointment the patients were booked to have a CT scan of the chest and abdomen to check for any metastasis or local recurrence plus blood test including baseline renal function creatinine. Dysphagia together with other symptoms was evaluated at each visit and a thorough physical examination was done. At every appointment the new investigation findings were compared with the first post treatment scans. At each appointment the degree of dysphagia plus radiologic and clinical factors were assessed. The patients’ survival was linked with the following factors: gender, disease site, tumor location, pathology, stage and size, ECOG status, and grade of dysphagia, treatment received, and treatment length. Clinical examination was done for all patients every time plus CT scans comparison. 60 STATISTICAL ANALYSIS Analysis was performed using the SAS statistical analysis software system (SAS Institute, Cary, NC, USA). Overall survival and dysphagia relief score were estimated based on a univariatecategorized analysis. These numbers were plotted and the Kaplan-Meier graph method was used for the description of survival analyses. In order to compare the two treatment strategies a log-rank test was used for survival analyses of variables as predictors. Univariate analysis for age, gender, pathology, tumor location, length, performance score, weight and treatment given on dysphagia free and overall survival was performed. Because of the large number of covariates observed only those that were significant on univariate analysis were included in the multivariate analysis. If the variables were too unevenly balanced or had a high percentage of missing data theywere not included into the multivariable procedure. The percentage of missing data was not recorded. The performance status was measured using the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale Performance. To test the hypotheses regarding the effect of treatments: HDRILBT alone and HDRILBT followed by Chemotherapy on overall survival, a Cox regression model was used for multivariate survival analyses. Pearson Chi-Square Tests were used and categorical prognostic data was evaluated based on chi-squared distribution where the expected cell counts were less than 5. ETHICS The study was approved by the Research Ethics Committee, McMaster University, Hamilton. 61 3.0 RESULTS In this study 132 patients with advanced esophageal cancer treated at Juravinski Cancer Centre, Hamilton Health Sciences Corporation from 2005-2008 were included. The demographic variables plus clinical variables which includes gender, disease site and length, dysphagia, ECOG status, weight loss, co-morbidities (heart problems) were analyzed. Table 2.3 shows a summary of the patient population characteristics. Table 2.3- Clinical Patient Characteristics Characteristics Number of patients, percentage (%) HDRILBT alone Number of patients, percentage (%) HDRILBT +ECF p- value Age at Diagnoses Mean Age: 71.41 Mean Age: 59.98 <0.0001 Gender Male n=101 Female n=31 72 (54.5%) 26 (19.7%) 29 (21.96%) 5 (3.7%) Disease Site GE junction n=24 Lower esophagus n=81 Mid esophagus n=17 Cervical esophagus n=5 Unspecified n=5 <0.0001 NS 17 (12%) 57 (43.1%) 16 (12.12%) 4 (3.03%) 4 (3.03%) 7 (5.3%) 24 (18.2%) 1 (0.75%) 1 (0.75%) 1 (0.75%) NS Co-morbidities None n=54 39 (29.54%) 15 (11.36%) Present n=78 59 (44.59%) 19 (14.39%) NS-Not Significant Pathological variables included tumor stage, pathology type, and treatment modalities. Histologically, the type of cancer was proven either squamous cell carcinomas (37 62 patients, 28%) or adenocarcinoma esophageal cancer (90 patients, 68.18%). Most patients had poorly differentiated carcinoma (77 patients, 58.3%). Tumor location on the esophagus included the upper esophagus, the middle esophagus, the lower esophagus, and the gastro-esophageal junction and any anastomosis place. At presentation some patients already had distant metastasis (74 patients, 56%) and nodal metastasis were present in 87 patients (65.9%) (Table 2.4) Table 2.4- Tumor Characteristics and Treatment Features Characteristics Treatment given Number of patients, percentage (%) HDRILBT alone 98 (74.25%) Number of patients, percentage (%) HDRILBT +ECF 34 (25.75%) Tumour pathology Adenocarcinoma n=90 Squamous n=37 63 (47.73%) 32 (24.24%) 27 (20.45%) 5 (3.70%) Adeno-squamous n=3 Unspecified n=2 2 (1.5%) 1 (0.75%) 1 (0.75%) 1 (0.75%) Grade Well n= 5 Moderate n=33 4 (3.03%) 26 (19.7%) 1 (0.75%) 7 (5.30%) Poorly differentiated n=77 60 (45.45%) 17 (12%) Unspecified n=51 42 (31%) 9 (6%) Distant Metastatic at presentation Absent n=58 Present n=74 Nodal Metastasis at presentation Absent n=45 Present n=87 NS-Not Significant p-values NS NS NS 44 (33.3%) 54 (40.9%) 14 (10.6%) 20 (15.15%) p<0.000 42 (31%) 56 (42.42%) 63 3 (2.3%) 31 (23.4%) The selection of patients receiving additional chemotherapy was based on performance status and age. The WHO (World Health Organization)/ECOG (Eastern Cooperative Oncology Group) score was an observer-rate scale that measured the patient performance status and ranges from 0 to 4 (Table 2.6). Table 2.6- WHO/ECOG SCORE 0 1 2 3 4 DESCRIPTION Full active Ambulatory, capable of light work In bed <50% of time, capable of self-care but not work In bed >50% of time, capable of only limited self care Completely bed ridden Out of 132 patients entered in the study, 52 were evaluated to have performance status 1 and 51 score of 2 (table 2.7). Table 2.7- Study Patients’ Performance Status ECOG Total number of patients, percentage (%) score Number of patients, HDRILBT alone Number of patients, HDRILBT +ECF 0 15 (11.36%) 10 5 1 52 (39.4%) 35 17 2 51 (38.6) 41 10 3 12 (9.1%) 10 2 4 2 (1.5%) 2 0 64 3.1) AGE Patients eligible for chemotherapy in addition to brachytherapy were younger than those who received brachytherapy alone. On analysis, age was a statistically significant factor (p<0.0001) (Figure 3.1). Figure 3.1- Pie graph showing age distribution of patients 65 3.2) GENDER The majority of the patients in the study were men i.e. 76.5% (101 cases out of 132) (Figure 3.2) Figure 3.2- Pie graph showing gender distribution of patients More male patients than female went on to have additional chemotherapy 21.96% vs. 3.7%. (Figure3.3) Figure 3.3- Pie graphs showing male and female distribution of patients studied for each treatment strategy 66 3. 3) TUMOUR LOCATION The tumor location and the influence on the survival rate were analyzed but it was not statistically significant. Most often the tumor was located mainly in the lower third of esophagus and GE junction (Figure 3.4) Figure 3.4- Pie graph showing tumor location . 67 3. 4) PATHOLOGY Histopathology was mainly adenocarcinoma (90/132) (68.2%)(Table 3.5). In the univariate analysis there was no correlation between survival rate and histology of the tumor. Histopathological reports were done in all cases based on endoscopic biopsy and gross specimen. Table 3.5- Tumor Pathology Tumour pathology Adenocarcinoma n=90 Squamous n=37 Other n=5 Percentage 68.2% 28.0% 3.8% Figure 3.6- Pie graph showing tumor pathology 3. 5) TUMOR LENGTH The length treated for patients included in the study had a median of 11 cm regardless of the treatment strategy. The tumor length was not a statistically significant factor. 68 3. 6) NODAL METASTASIS Nodal metastasis was present in 55.8% (87/132) of esophageal cancer patients. The patients’ charts were reviewed to identify patient with existing nodal metastasis (Figure 3.7 and 3.8). The data were analyzed and showed it to be strongly statistically significant (p<0.000). Figure 3.7- Distribution of Nodal Metastasis for patient receiving HDRILBT only Figure 3.8: Distribution of Nodal Metastasis for patient receiving HDRILBT plus Chemotherapy 69 3. 7) Esophagus cancer patients were divided in two categories: with or without distant metastasis (Figure 3.9). Even though the expectation was that patients with no distant metastasis 43.9% (58/132 would do better compared with the ones with metastasis this was not strongly significant. Figure 3.9- Distant Metastases 70 3. 8) TREATMENT GIVEN 98 (74.25%) patients underwent HDR brachytherapy alone and 34 (25.75%) patients underwent HDR brachytherapy followed by chemotherapy (Figure 3.10). Figure 3.10- Distribution of treatment given and number of patients 3. 9) ECOG SCORE The ECOG performance status was higher for HDRILBT plus chemotherapy group of patients. This reached statistically significance, a p-value of 0.0014. Patients treated with HDRILBT and received additional ECF were in better condition status than those who received HDRILBT alone. 71 INFLUENCE OF DYSPHAGIA ON SURVIVAL All patients (n=132, 100%) had near total or total dysphagia at presentation. Relief of dysphagia was seen in more than 90% of patients. The improvement of dysphagia was at least by 2 grades within 6 weeks of brachytherapy. DFS improved in patients who received ECF chemotherapy (mean 232 days) when compared with those who received HDRILBT alone (mean 182 days). However, this difference was not statistically significant (p=0.2954) Table 3.11- Dysphagia free survival for both treatment modalities Mean DFS (by 2 grades) 182 days 232 days HDRILBT alone HDRILBT + ECF Chemotherapy Figure 3.12- Dysphagia Free Survival DFS Percent Figure 1- Dysphagia Free Survival 100% 80% 60% 40% 20% 0% 0 60 Days Survived Brachytherapy 120 180 240 300 360 Days Survived Brachytherapy+Chemotherapy --------------Brachytherapy; ----------------Brachytherapy plus Chemotherapy 72 On univariate analysis there was no impact of any prognostic marker on dysphagia free survival. On multivariate analysis the HDRILBT treatment with additional ECF chemotherapy had a significant impact on DFS (p= 0.0462). 73 OVERALL SURVIVAL Overall survival improved in patients who received additional ECF chemotherapy (p= 0.0010) than HDRILBT alone. OS for HDRILBT + ECF was 266 days compared to HDRILBT alone 155 days (p = 0.0010). An important observation, additional ECF chemotherapy had a considerably impact on OS (p=0.0007). On multivariate analysis tumor length (p=0.02003) and nodal metastases at presentation (p=0.000) were impacted on overall survival. Table 3.14- Overall survival for both treatment modalities Overall Survival 155 days 266 days HDRILBT alone HDRILBT + ECF Chemotherapy Figure 3.13- Overall Survival OS Figure 2- Overall Survival 100% Percent 80% 60% 40% 20% 0% 0 60 Days Survived Brachytherapy 120 180 240 300 360 Days Survived Brachytherapy+Chemotherapy --------------Brachytherapy; ----------------Brachytherapy plus Chemotherapy 74 On univariate analysis patients undergoing brachytherapy with additional ECF chemotherapy were younger age (p<0.001) and with a better performance status (p=0.0041) compared to those patients receiving brachytherapy alone. 75 COMPLICATIONS Complications of treatment occurred in both treatment strategies. There were 11 cases of stricture, with 11 after brachytherapy alone and 4 after the addition of chemotherapy after brachytherapy. None was life threatening and they were successfully treated. Table 3.15- Complications for both treatment modalities HDRILBT alone Stricture Median Time to occur 7 106 days HDRILBT alone Fistulae Median Time to occur 4 0 HDRILBT+ECF CHEMOTHERAPY 4 110 days HDRILBT+ECF CHEMOTHERAPY 0 - TOXICITIES Table 3.16- Total number of toxicities for both treatment modalities together Toxicities Number of occurrences GI 25 Neurotoxicity 2 Nephrotoxicity 2 All patients finished all 3 fractions of high dose rate brachytherapy. ECF chemotherapy was delivered in a range from 1-10 cycles. 18 patients completed at least 3 cycles. Most of the toxicities were caused by the 5 Fluorouracil induced mucositis. The side effects were related mostly to gastro-intestinal tract. Complications because of Cisplatin were rare and mostly neuro- and nephro- toxicities. Epirubicin did not give any cardio side effect to any patient. 76 4.0 DISCUSSION Many studies have shown brachytherapy to be widely used for palliation of dysphagia due to advanced esophageal cancer (Table 4.1). Table 4.1- Review HDRILBT with literature AUTHOR CONCLUSION BHATT, 2012 Older patients with increased dysphagia tolerated HDRILBT well and treatment was effective. BERGQUIST 2005 HDRILBT compared with stent: rapid improvement of dysphagia with the stent but after 1 month both treatment modalities have the same improvement rate. Better QOL with brachytherapy than stent FONTANESSI, 1989 HDRILBT decreased dysphagia, no further treatment for obstruction needed. HARVEY, 1993 Comparison between HDRILBT and EBRT: brachytherapy is an effective modality for older patient, with poor physical condition HOMS, 2002, 2006 HDRILBT is effective, no major complications but recurrent and persistent dysphagia occurs that requires further treatment (e.g. stent) HOMS, 2005 HDRILBT compared with stent: rapid improvement of dysphagia with the stent but after 1 month both treatment modalities have the same improvement rate JAGER, 1992 Single HDRILBT of 15Gy dose was appropriate for dysphagia relief KAUL, 1990 Single HDRILBT of 12Gy dose was effective in dysphagia relief for elderly patients 77 KULHAVY, SUR and LEVIN, 1995 HDRILBT dose between 12-15Gy gives least morbidity LOW, 1992 Similar results between HDRILBT and laser treatment but retreatments were 3 times higher for laser group SUR, 1991 HDRILBT with 12Gy given in 2 fractions had a high survival rate and more effective than intubation in dysphagia relief SUR, 1996 HDRILBT best palliative modality, optimal dose 16Gy/2 fractions or 18Gy/3 fractions SUR, 2001 Patient received either HDRILBT or HDRILBT with EBRT-no difference in survival between the 2 treatment strategies SKOWRONEK, 2004 HDRILBT dose 22.5Gy in 3 fractions effective in improvement of dysphagia WEI-BO-YIN, 1989 Combination of HDRILBT +EBRT better survival results than EBRT alone WEE, 1994 HDRILBT dose of 15Gy in 1 or 2 treatment. Same dysphagia improvement FLEISHMAN, 2006 HDRILBT can be used instead of EBRT with same palliative effect ROWLAND, 1985 HDRILBT more effective than intubation in dysphagia relief The role of additional chemotherapy to high dose rate intraluminal brachytherapy in improving DFS has not been reported before. Sur et al. [128] have previously examined the role of chemosensitization with brachytherapy in advanced esophageal cancer. The incidence of toxicities in form of stricture and fistulae significantly increased when 78 chemotherapy with 5 Fluorouracil was used with brachytherapy. Also strictures occurred earlier and were more recalcitrant and difficult to dilate when chemotherapy was used as a sensitizer. The study recommended that the two not to be used together. Patients with metastatic esophageal cancer present with dysphagia and weight loss. In these patients the first aim of treatment is to restore swallowing. Brachytherapy is an effective method of palliation to relief dysphagia [127-130]. Dysphagia relief is sustained in more than 70% cases for many months after treatment. HDRILBT can be done in all patients regardless of their performance status. Unlike brachytherapy chemotherapy alone can only be offered to selected patients who are in good general condition. A RCT is therefore not feasible that can compare chemotherapy (CCT) alone to HDRILBT alone as majority of patients would not be in a condition to receive palliative CCT due to their poor performance status. Patients with metastatic esophageal cancer present with dysphagia and weight loss. In these patients the first aim of treatment is to restore swallowing. Brachytherapy is an effective method of palliation to relief dysphagia [127-130]. Dysphagia relief is sustained in more than 70% cases for many months after treatment. HDRILBT can be done in all patients regardless of their performance status. Unlike brachytherapy chemotherapy alone can only be offered to selected patients who are in good general condition. A RCT is therefore not feasible that can compare CCT alone to HDRILBT alone as majority of patients would not be in a condition to receive palliative CCT due to their poor performance status. 79 For some patients with esophageal cancer who have metastatic cancer and are in good general condition, chemotherapy is often used after brachytherapy especially if the patient is young (as was seen in this series). In these patients the value of additional multiagent chemotherapy (ECF in this series) was never examined. This study shows that additional ECF chemotherapy in selected patients improves DFS and significantly improves OS. The incidence of complication and toxicity related to chemotherapy is reasonable and the treatment is well tolerated in the majority of patients. A break of 3-4 weeks between brachytherapy and chemotherapy is needed to improve the outcomes. This interval allows tissue healing and recovery post brachytherapy, improves nutrition and the general condition of the patient. As a result patients tolerate treatment a lot better. The incidence of complications related to radiation i.e., strictures and fistulae does not increase by the additional chemotherapy especially if the break is given allowing tissue recovery. Chemotherapy after brachytherapy should therefore offered to all patients with esophageal cancer who are in good general condition. This study is a retrospective analysis of a prospective database. Being retrospective this study has limitations in selection bias and outcome measures. A well designed RCT is indicated. 80 5.0 CONCLUSION High Dose Rate Intraluminal Brachytherapy is an effective modality of palliation in advanced esophageal cancer patients. 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