Upper Oesphageal Neoplasms

1. Upper Oesphageal Neoplasms Anja Lieder Specialist Registrar, Northern Deanery SpR Teaching Hallo. I am going to talk about malignant neoplasms of the upper oesophagus. Hallo. I am going to talk about malignant neoplasms of the upper oesophagus.

2. Lesson Plan 1. Anatomy 2. Epidemiology/Pathology 3. Making a Diagnosis / Staging 4. Therapy Options 5. Pharyngeal Pouch and Carcinoma This presentation will be centred on carcinoma of the oesophagus. This is because carcinoma of the oesophagus makes over 99% ot neoplasms of the oesophagus, with benign tumours extemely rare. In particular, I will try to concentrate on carcinoma of the upper oesophagus. We will go briefly though anatomy, some pathology, and how to make a diagnosis and stage an oesophageal cancer. We will spend a little more time on the different treatment options available, and last not least. I will talk about carcinoma of a pharyngeal pouch , which, although rare and not strictly speaking in the oesophagus, we may see in our ENT practice. This presentation will be centred on carcinoma of the oesophagus. This is because carcinoma of the oesophagus makes over 99% ot neoplasms of the oesophagus, with benign tumours extemely rare. In particular, I will try to concentrate on carcinoma of the upper oesophagus. We will go briefly though anatomy, some pathology, and how to make a diagnosis and stage an oesophageal cancer. We will spend a little more time on the different treatment options available, and last not least. I will talk about carcinoma of a pharyngeal pouch , which, although rare and not strictly speaking in the oesophagus, we may see in our ENT practice.

3. Oesophagus from lower border of cricoid cartilage (C6) to cardiac orifice 25cm long in adults 3 constrictions M. cricopharyngeus (15cm) Aortic arch/main bronchus (23cm) Diaphragm (40cm) 4 layers: Mucosa Submucosa muscle, outer fibrous layer The oesophagus is a hollow visceral organ connecting the pharynx with the stomach and reaches from the lower border of the cricoid cartilage at C6 to the cardiac orifice of the stomach. It it 25cm long in adults. In its course, there are 3 narrowings. These are the upper oesophageal sphincter at the cricopharyngeus muscle at 15 cm from incisiors, the aortic arch and main bronchus crossing the oesophagus at 23cm and the oesophagus piercing the diaphragm at 40cm. The organ consists of 4 layers: mucosa, submucosa, muscle and an outer fibrous layer. The mucosa is nonkeratinising stratifies squamous epithelium in continuation with the pharynx. The lamina propria mucosae contains loose connective tissue, elastic fibres, gut-associated lymphoid tissue (GALT) and parasympathetic nerve fibres underneath. There is a thin muscularis mucosae layer wrapping the mucosa. The submucosal layer contains mucosal glands. The muscular layer, called muscularis propria, consists of two layers and gets thicker as it descends. The inner layer is circular in its orientation and is striated muscle in the upper third, smooth and striated muscle in the middle third, and predominantly smooth muscle in the lower third. The outer layer is longitudinal in its orientation and is complete except for a small dehiscence at its superior end. The oesophagus is a hollow visceral organ connecting the pharynx with the stomach and reaches from the lower border of the cricoid cartilage at C6 to the cardiac orifice of the stomach. It it 25cm long in adults. In its course, there are 3 narrowings. These are the upper oesophageal sphincter at the cricopharyngeus muscle at 15 cm from incisiors, the aortic arch and main bronchus crossing the oesophagus at 23cm and the oesophagus piercing the diaphragm at 40cm. The organ consists of 4 layers: mucosa, submucosa, muscle and an outer fibrous layer. The mucosa is nonkeratinising stratifies squamous epithelium in continuation with the pharynx. The lamina propria mucosae contains loose connective tissue, elastic fibres, gut-associated lymphoid tissue (GALT) and parasympathetic nerve fibres underneath. There is a thin muscularis mucosae layer wrapping the mucosa. The submucosal layer contains mucosal glands. The muscular layer, called muscularis propria, consists of two layers and gets thicker as it descends. The inner layer is circular in its orientation and is striated muscle in the upper third, smooth and striated muscle in the middle third, and predominantly smooth muscle in the lower third. The outer layer is longitudinal in its orientation and is complete except for a small dehiscence at its superior end.

4. Pharyngo-oesophageal junction Here is a picture of the relation between the upper oesophagus and the larynx and pharynx. The upper oesophageal spincter is at level C6 and the level of the cricoid cartilage. Here is a picture of the relation between the upper oesophagus and the larynx and pharynx. The upper oesophageal spincter is at level C6 and the level of the cricoid cartilage.

5. Epidemiology Over 99% of oesophageal tumours are malignant. Only half a percent of oesophageal tumours are benign, most of them are leiomyomas or gastrointestinal stromal tumours. The vast majority of oesophageal malignant tumours are carcinoma. Carcinoma of the oesophagus has one of the fastest growing incidences of the developed world and is still one of the deadliest cancers. The vvast majority of malignant oesophageal tumours are carcinoma, and I will concentrate my presentation on on these. Its 5 year survival rate overall is only 8% in the United Kingdom. The 5-year survival rate rises to 20-25% for resectable cancers. It is more common in males, and occurs in the older population, with the median age being 60 years. Over 99% of oesophageal tumours are malignant. Only half a percent of oesophageal tumours are benign, most of them are leiomyomas or gastrointestinal stromal tumours. The vast majority of oesophageal malignant tumours are carcinoma. Carcinoma of the oesophagus has one of the fastest growing incidences of the developed world and is still one of the deadliest cancers. The vvast majority of malignant oesophageal tumours are carcinoma, and I will concentrate my presentation on on these. Its 5 year survival rate overall is only 8% in the United Kingdom. The 5-year survival rate rises to 20-25% for resectable cancers. It is more common in males, and occurs in the older population, with the median age being 60 years.

6. Pathology Of course, tehre are two different types of Oesophageal carcinoma. The squamous cell carcinoma occurs in the proximal and middle oesophagus, while the adeno-carcinoma occurs in the distal oesophagus and at the gastro-oesophageal junction. This talk will focus on the malignancy of the upper oesophagus and therefore the most of what follows will be on squamous cell carcinoma. Squamous carcinoma used to be a lot more common, but now the incidence of adenocarcinoma has surpassed that of squamous cell carcinoma in many parts of the developed world, including the UK and the US. Countries where the incidence of SCC is still higher include Russia, China, Iran and TurkeyOf course, tehre are two different types of Oesophageal carcinoma. The squamous cell carcinoma occurs in the proximal and middle oesophagus, while the adeno-carcinoma occurs in the distal oesophagus and at the gastro-oesophageal junction. This talk will focus on the malignancy of the upper oesophagus and therefore the most of what follows will be on squamous cell carcinoma. Squamous carcinoma used to be a lot more common, but now the incidence of adenocarcinoma has surpassed that of squamous cell carcinoma in many parts of the developed world, including the UK and the US. Countries where the incidence of SCC is still higher include Russia, China, Iran and Turkey

7. Risk Factors Risk factors for both types of oesophageal carcinoma includeRisk factors for both types of oesophageal carcinoma include

8. Presentation The main The main

9. Diagnostic Workup The diagnostic workup begins with a history and thorough examination, of course, and blood tests to check for anaemia, malnutrition and clotting abnormalitiesThe diagnostic workup begins with a history and thorough examination, of course, and blood tests to check for anaemia, malnutrition and clotting abnormalities

10. Staging

11. Treatment Options

12. Treatment Options The mainstay of the treatment is surgery, but the tumour needs to be resectable and the patient must be medically fit enough to survive the procedure. There are two main surgical options for oesophagectomy. The transthoracic oesophagectomy after Ivor Lewis was first performed in 1946 and requires a laparotomy and a thoracotomy. This procedure offers the advantage of regional lymph node dissection under direct vision, but has a significant pulmonary complication rate and high perioperative morbidity, around 18% (Ott et al in a study of 240 patients). Some centres now perform a less invasive procedure by replacing the laparatomy with a laparoscopy and report a much lower morbidity (0 in-hospital mortality reported by Hamouda et al in 75 patients). Other surgeons have pioneered a thoracoscopic as well as laparoscopic procedure (Nguyen 2001). Nguyen reported a major complication rate of 12.5% and a mortality of 2.9% in a study of 104 patients in 2008. Transhiatal oesophagectomy was first performed in 1976 and is reported to ne less invasive and have fewer complications. The biggest series of 200o patietns is reported to have a major complication rate of around 6-8%, mostly wound dehiscence. The mainstay of the treatment is surgery, but the tumour needs to be resectable and the patient must be medically fit enough to survive the procedure. There are two main surgical options for oesophagectomy. The transthoracic oesophagectomy after Ivor Lewis was first performed in 1946 and requires a laparotomy and a thoracotomy. This procedure offers the advantage of regional lymph node dissection under direct vision, but has a significant pulmonary complication rate and high perioperative morbidity, around 18% (Ott et al in a study of 240 patients). Some centres now perform a less invasive procedure by replacing the laparatomy with a laparoscopy and report a much lower morbidity (0 in-hospital mortality reported by Hamouda et al in 75 patients). Other surgeons have pioneered a thoracoscopic as well as laparoscopic procedure (Nguyen 2001). Nguyen reported a major complication rate of 12.5% and a mortality of 2.9% in a study of 104 patients in 2008. Transhiatal oesophagectomy was first performed in 1976 and is reported to ne less invasive and have fewer complications. The biggest series of 200o patietns is reported to have a major complication rate of around 6-8%, mostly wound dehiscence.

13. Treatment Options Radiotherapy or CHemoradiotherapy is reserved for those with non-resectable tumours or who are unfit for surgery. It is palliative, but a few long-term survivors have been reported. Herskovic found in a study of 121 patients with inoperable disease that Chemoradiotherapy was superior to radiotherapy and increased survival by 12 months (compared to doing nothing). Sykes and colleages reported a 5-year survival rate of 21% in 101 patients with inoperable oesophageal carcinoma, with 20 patients surviving three years or longer. Radiotherapy or CHemoradiotherapy is reserved for those with non-resectable tumours or who are unfit for surgery. It is palliative, but a few long-term survivors have been reported. Herskovic found in a study of 121 patients with inoperable disease that Chemoradiotherapy was superior to radiotherapy and increased survival by 12 months (compared to doing nothing). Sykes and colleages reported a 5-year survival rate of 21% in 101 patients with inoperable oesophageal carcinoma, with 20 patients surviving three years or longer.

14. Treatment Options Perioperative chemotherapy has been shown to improve survival rates when combined with surgery. In the first of such studies, Kelsen and colleagues showed in a study of 440 patients that there was no significant difference between Surgery alone and Surgery plus chemotherapy with Cisplatin and 5-FU in a two-year observation period (USA Intergroup 113 trial). However, long-term follow up showed that chemotherapy improved 5-year survival in patients with a R0 resection. In the UK, an MRC trial of 802 patients used perioperative chemotherapy in the form of combination of Epirubicin, Cisplatin and 5-Fluoruracil. 802 patients joined the study, and overall survival after 2 years was improved in the chemotherapy group (43% versus 34% in non-chemo) regardless of R0 resection or not. A second MRC trial known as the MAGIC trial was completed by Cunningham and others but this included gastic carcinoma as well as cancer of the lwoer oesophagus but not the upper oesophagus. Here, in just over 500 patients, the chemotherapy decreased tumour size and stage and improved overall survival. More current trials are adding anti-VEGF antibody but there are no results yet. And finally, a meta-analysis of 8 trials performed by Gebski and colleagues showed an absolute survival benefit of 7% for chemotherapy and surgery compared to surgery alone. A second meta-analysis including 9 RCT�s showed a smaller but significant benefit for perioperative chemotherapy over surgery alone at five years. Perioperative chemotherapy has been shown to improve survival rates when combined with surgery. In the first of such studies, Kelsen and colleagues showed in a study of 440 patients that there was no significant difference between Surgery alone and Surgery plus chemotherapy with Cisplatin and 5-FU in a two-year observation period (USA Intergroup 113 trial). However, long-term follow up showed that chemotherapy improved 5-year survival in patients with a R0 resection. In the UK, an MRC trial of 802 patients used perioperative chemotherapy in the form of combination of Epirubicin, Cisplatin and 5-Fluoruracil. 802 patients joined the study, and overall survival after 2 years was improved in the chemotherapy group (43% versus 34% in non-chemo) regardless of R0 resection or not. A second MRC trial known as the MAGIC trial was completed by Cunningham and others but this included gastic carcinoma as well as cancer of the lwoer oesophagus but not the upper oesophagus. Here, in just over 500 patients, the chemotherapy decreased tumour size and stage and improved overall survival. More current trials are adding anti-VEGF antibody but there are no results yet. And finally, a meta-analysis of 8 trials performed by Gebski and colleagues showed an absolute survival benefit of 7% for chemotherapy and surgery compared to surgery alone. A second meta-analysis including 9 RCT�s showed a smaller but significant benefit for perioperative chemotherapy over surgery alone at five years.

15. Treatment Options However, the survival of patients even with a resectable tumour is rarely less than 25%. Some of the studies of radiotherapy argue a similar rate of survival could be achieved without surgery. Combining surgery and radiotherapy has been investigated to see if they could achieve a higher cure rate. There have been around 10 RCT in the past 20 years, most of them with around hundred patients in total or less. In recent years, many trials had more adenocarcinoma of the oesophagus, reflecting the rising incidence of adenocarcinoma. The most successful trial was conducted by Walsh and colleagues in Ireland and included 113 patients, who had perioperative Cisplating and 5-Fluorouracil in the 7 days leading up to surgery as well as 40Gy in 15 fractions radiotherapy. A further cycle of chemotherapy was given 6 weeks after surgery. This led to increased 3-year survival of 32% over 6% with surgery alone, although one can argue that the surgery alone survival is very low when compared to other surgery alone arms. For example, the Intergroup 113 trial had a surgery alone survival of 26%. The only other trial that showed a definite improvement using the multimodal approach was a study by Tepper and colleagues in 2008, where a similar regime of Cisplatin and 5-FU plus 50Gy neoadjuvant therapy led to significantly improved median survival of 4.5 years compared to 1.8 years on surgery alone. But poor accrual led to early termination of treatment, and only 56 patietns competed the trimodal therapy arm. Again, several meta-analyses have been done to evaluate trimodal therapy. In analyses by Urschel and colleagues and Fiorica and colleagues, 3 year survival was improved on trimodal therapy. The report by Gebski had similar finding, with a 13% absolute survival difference at 2 years. However, the survival of patients even with a resectable tumour is rarely less than 25%. Some of the studies of radiotherapy argue a similar rate of survival could be achieved without surgery. Combining surgery and radiotherapy has been investigated to see if they could achieve a higher cure rate. There have been around 10 RCT in the past 20 years, most of them with around hundred patients in total or less. In recent years, many trials had more adenocarcinoma of the oesophagus, reflecting the rising incidence of adenocarcinoma. The most successful trial was conducted by Walsh and colleagues in Ireland and included 113 patients, who had perioperative Cisplating and 5-Fluorouracil in the 7 days leading up to surgery as well as 40Gy in 15 fractions radiotherapy. A further cycle of chemotherapy was given 6 weeks after surgery. This led to increased 3-year survival of 32% over 6% with surgery alone, although one can argue that the surgery alone survival is very low when compared to other surgery alone arms. For example, the Intergroup 113 trial had a surgery alone survival of 26%. The only other trial that showed a definite improvement using the multimodal approach was a study by Tepper and colleagues in 2008, where a similar regime of Cisplatin and 5-FU plus 50Gy neoadjuvant therapy led to significantly improved median survival of 4.5 years compared to 1.8 years on surgery alone. But poor accrual led to early termination of treatment, and only 56 patietns competed the trimodal therapy arm. Again, several meta-analyses have been done to evaluate trimodal therapy. In analyses by Urschel and colleagues and Fiorica and colleagues, 3 year survival was improved on trimodal therapy. The report by Gebski had similar finding, with a 13% absolute survival difference at 2 years.

16. New directions in therapy

17. Carcinoma ex pharyngeal pouch Finally, I would like to talk briefly about a type of carcinoma that we may see in ENT, although it is reported to be very rare. Pharyngeal pouches, although not strictly in the oesophagus, can develop sqamous cell carcinoma. It is thought to occur by chronic irritation of the pharyngeal pouch mucosa by food particles, leading to carcinoma in situ and eventually to carcinoma. The largest study was conducted by Bradley 10 years ago, who found 2 carcinomata in his patient group of 91 treated for a pharyngeal pouch. Both had the pouch excised and survived long-term, one being followed up for 3 years, the other 11 years tumour free. Other case series suggested that the carcinoma can still occur after endoscopic treatment, such as the Dohlman�s procedure (division of bar cold steel or laser), but only one case after stapling has been reported in the literature so far. In excised sac specimens, a carcinoma in situ is sometimes found. If symptoms suddenly change for the worse, a carcinoma ex pouch should be suspected, even if the patient hasd had previous treatment for a pouch, Treatment is by excision of the pouch, Bradley stipulates in his 1999 review that patients younger than 65 years should, for this reason, have their pouch ecxcised. He also stresses the importance of long-term follow up after endoscopic treatment of pharyngeal pouch. Finally, I would like to talk briefly about a type of carcinoma that we may see in ENT, although it is reported to be very rare. Pharyngeal pouches, although not strictly in the oesophagus, can develop sqamous cell carcinoma. It is thought to occur by chronic irritation of the pharyngeal pouch mucosa by food particles, leading to carcinoma in situ and eventually to carcinoma. The largest study was conducted by Bradley 10 years ago, who found 2 carcinomata in his patient group of 91 treated for a pharyngeal pouch. Both had the pouch excised and survived long-term, one being followed up for 3 years, the other 11 years tumour free. Other case series suggested that the carcinoma can still occur after endoscopic treatment, such as the Dohlman�s procedure (division of bar cold steel or laser), but only one case after stapling has been reported in the literature so far. In excised sac specimens, a carcinoma in situ is sometimes found. If symptoms suddenly change for the worse, a carcinoma ex pouch should be suspected, even if the patient hasd had previous treatment for a pouch, Treatment is by excision of the pouch, Bradley stipulates in his 1999 review that patients younger than 65 years should, for this reason, have their pouch ecxcised. He also stresses the importance of long-term follow up after endoscopic treatment of pharyngeal pouch.

18. References Khushalani NL 2008: Cancer of the Esophagus and Stomach. Mayo Clin Proc; 83:712-722 Netter�s Head and Neck Anatomy University of Michigan Thoracic Surgery (http://surgery.med.umich.edu/thoracic) Cancer research UK Cancer Statistics (http://info.cancerresearchuk.org/cancerstats) Hamouda et al 2009: Perioperative outcomes after transition from conventional to minimally invasive Ivor-Lewis esophagectomy in a specialized center, Surgical Endoscopy Ott et al 2009: Surgical factors influence the outcome after Ivor-Lewis esophagectomy with intrathoracic anastomosis for adenocarcinoma of the esophagogastric junction: a consecutive series of 240 patients at an experienced center Nguyen et al 2001: Minimally invasive Ivor Lewis esophagectomy. Ann Thorac Surg; 72:593-6 Nguyen et al 2008: Minimally invasive esophagectomy: lessons learned from 104 operations. Ann Surg 228:1081-91 Orringer et al 2007: Two thousand transhiatal esophagectomies: changing trends, lessons learned. Ann Surg 246: 363-72 Sykes et al 1998: Radical radiotherapy for carcinoma of the oesophagus: an effective alternative to surgery. Radiother Oncol 48:15-21 Acharya et al 2006: Carcinoma arising in a pharyngeal pouch previously treated by endoscopic stapling. Laryngoscope 116: 1043-5 Bradley et al 1999: Pharyngeal pouch carcinoma: real or imaginary risks? Ann Otol Rhinol Laryngol 108: 1027-32

19. References Herskovic et al 1992: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus.N Engl J Med 326:1593-8 Kelsen et al 1998: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. NEngl J Med 339:1979-84 Kelsen et al 2007: Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer.J Clin Oncol 3719-25 MRC 2002: Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 359:1727-33 Cunningham et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355: 11-20 Gebski et al 2007: Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 8:226-234 Thirion et al 2007: MetaAnalysis of Chemotherapy in Esophagus Cancer Collaborative Group. JClin Oncol 25(18S) Walsh et al 1996: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Eng J Med 335: 462-467 (Erratum published 1999 � labelling of figures) Tepper et al 2008: Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26:1086-92 Urschel &Vasan 2003. A meta-analysis of randomised controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 185: 538-543 Fiorica et al 2004. Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut 53: 925-930