The effect of neo-adjuvant chemotherapy on the discrepancy between the endoscopic ultrasonography (EUS) and pathological staging of oesophageal cancer MS Dorrington2, JH Saunders1, 2, K Ragunath3 and SL Parsons1 Dept. of Upper GI Surgery, Nottingham University Hospitals NHS Trust1 Division of Cancer Biology, School of Medicine, University of Nottingham2 NDDC and NIHR Biomedical Research Unit, Nottingham University Hospitals NHS Trust3 Welcome all to my presentation, my name is Matt Dorrington, the presenter. I am a non-clinician working as a Research Associate at the University of Nottingham so I would like to make an apology in advance if my clinical knowledge is not as good as yours- so please be considerate to me with the questions at the end. But we do have Mr John Saunders in the audience who can help. So the title of this presentation is the effect of neo-adjuvant chemotherapy on the discrepancy between the EUS and pathological staging of oesophageal cancer.

Introduction: EUS- high sensitivity and specificity determining TN stage (Puli et al, 2008, WJ Gastro). However there is still a discrepancy between EUS and the pathological TN staging. EUS plays an important role in the preoperative staging of oesophageal cancer and is highly sensitive and specific when determining TN stage. However there is still a discrepancy between EUS and the pathological TN staging. So the seminal paper in the literature by Puli et al 2008 in the world journal of Gastroenterology quoted that the T stage by EUS is 81% sensitive & 99% specific. N stage by EUS is 84% sensitive. But this paper was a meta-analysis before neo-adjuvant chemotherapy was routinely used.

Introduction continued: Majority of patients now undergo neo-adjuvant chemotherapy prior to resection which may result in downstaging the tumour if they respond to chemotherapy but may also lead to disease progression. We sought to determine whether the patient’s response to chemotherapy correlated with a difference in staging between EUS and pathology. Today, the majority of patients now undergo neo-adjuvant chemotherapy prior to resection which may result in downstaging the tumour if they respond to chemotherapy but may also lead to disease progression if the patient does not respond. We sought to determine whether the patient’s response to chemotherapy correlated with a difference in staging between EUS and pathology.

Background: Carcinoma of the oesophagus is the eighth commonest cancer. 8,500 individuals/ year are diagnosed with oesophageal cancer in the UK. Two main types: adenocarcinoma and squamous cell carcinoma. To set the scene for those of you not familiar with the disease, cancer of the oesophagus is the 8th most commonest cancer with approx. 8,500 individuals being diagnosed a year in the UK alone. There are two main types: The most common in the western world & in the UK being adenocarcinoma but globally, squamous cell carcinoma is the most common. Proximal Oesophagus Stomach Distal

Oesophageal cancer patient pathway overview: 1. Symptoms: i.e. dysphagia, weight loss. GP visit/referral. 2. Endoscopy- Biopsies taken, diagnosis confirmed. 3. MDT discussions– staging investigations and treatments outlined. 4. Staging (TNM) investigations- PET scan, CT scan, EUS, Staging laparoscopy. 5. Preoperative therapy i.e. neo-adjuvant-chemotherapy/ RT. 6. Oesophageal resection- subsequent histological examination Pathological TNM & tumour regression grade (TRG) determined. 7. Post-operative therapy i.e- adjuvant-chemotherapy. 8. Patient follow-up - Overall 13% survival at 5 years. So here is the typical oesophageal cancer patient pathway. When cancer of the oesophagus has been conformed in a patient, a number of staging investigations will be carried out including an EUS to determine a pre-treatment TNM which will aid in outlining a patients treatment options and prognosis. If a patient is treatable they will likely have pre-operative treatment such as neo-adjuvant chemotherapy, a resection and maybe post-operative therapy depending on the cancer type. The resection is where the pathological TN and Tumour regression grade is determined and the perceived accuracy of EUS staging is determined by a comparison between EUS TN with the pathological TN stages.

Pre-operative treatment response -Tumour regression grade (TRG): Mandard tumour regression grade (TRG) determines pathological response to chemotherapy. 1-3 is a response to chemotherapy. 4-5, no response. The mandard tumour regression grade is what pathologists use to determine the relative response to neo-adjuvant chemotherapy. It is a subjective scale measured 1-5. 1 to 3 being considered a response to chemotherapy (see photo A) and 4 to 5 considered a non-response (see photo B). This is a helpful measure as it can help us determine a relationship between chemotherapy and TN discrepancies.

Aim: With the routine use of neo-adjuvant chemotherapy, we sought to examine the effect of this on the discrepancy between EUS pre-treatment TN staging and final pathological TN assessment. With the routine use of neo-adjuvant chemotherapy, we sought to examine the effect of this on the discrepancy between EUS pre-treatment TN staging and final pathological TN assessment.

Methods: Cohort of 107 patients, Nottingham July 2011-2014, who underwent a staging EUS, neo-adjuvant chemotherapy, resection and histological examination. EUS TN & histological TNM with TRG was compared. Sub-divided into respective TRG groups: 1-3 chemo responders (n=39) and 4-5, non-responders (n=68). If the difference between EUS and pathology TN stage was greater than 1, the patient was considered to have been grossly over or under-staged. Using the formal hospital databases and going though many patient notes a cohort of 107 patients treated at Nottingham between July 2011-2014, each patient had a staging EUS, neoadjuvant chemotherapy, resection and histological examination. The EUS TN stage & histological TN with TRGs were compared. The cohort was sub-divided into their TRG groups: 1-3 chemo responders (n=39) and 4-5, non-responders (n=68). If the difference between EUS and pathology TN stage was greater than 1, the patient was considered to be grossly over or under-staged.

Results -explained EUS Path  vs T0 T1 T2 T3 T4 Path N0 N1 N2 N3 N4 So I need to explain how I will illustrate the results…example.

EUS  vs T0 T1 T2 T3 T4 Path N0 N1 N2 N3 N4 I have also used a traffic light system to help further…the green illustrates the EUS T and N matching the pathological T and N- the classical method of showing EUS accuracy

EUS  vs T0 T1 T2 T3 T4 Path N0 N1 N2 N3 N4 The amber illustrates an over or understage but not gross over and under stage

However, the red on the right shows a gross EUS over-stage…  vs T0 T1 T2 T3 T4 Path N0 N1 N2 N3 N4 However, the red on the right shows a gross EUS over-stage…

And the red here shows a gross EUS under-stage  vs T0 T1 T2 T3 T4 Path N0 N1 N2 N3 N4 And the red here shows a gross EUS under-stage

Number of gross T/ N EUS vs Path over or under stage cases Results: TRG 1-3 (n= 39) EUS  vs T0 T1 T2 T3 T4 5 7 2 Path 4 1 3 N0 N1 N2 N3 N4 13 Number of gross T/ N EUS vs Path over or under stage cases T stage N stage Over-staged Under-staged 18 1 3 And here are the results…in chemo responders TRG 1-3 category- the T stage of the cancer was over-staged in approx. 50% of cases… point, which could suggest the response to chemotherapy. The N stage only three were over-staged.

Number of gross T/ N EUS vs Path over or under stage cases Results: TRG 4-5 (n= 68) EUS  vs T0 T1 T2 T3 T4 Path 2 1 8 47 5 N0 N1 N2 N3 N4 13 7 3 4 10 Number of gross T/ N EUS vs Path over or under stage cases T stage N stage Over-staged Under-staged 2 1 4 10 In TRG 4-5 category- there were distinct differences in the N staging in 20% of the cases, and patients were almost twice as frequently under-staged then over-staged. The under staging particularly of N can suggest disease progression and chemo in these patients has not worked pathologically.

Potential study limitations: Incomplete examinations. EUS is operator dependent. Discrepancies between pathologists during assessment.

Conclusions: There is frequently a difference between pre and post treatment TN staging, affecting the perceived staging accuracy of EUS. Results would suggest that this difference is driven by response to neo-adjuvant chemotherapy. What do the results tell us? Well…Where there is chemotherapy response, EUS staging is frequently altered. Of the none chemo responders- disease progression can result in a perceived EUS under-staging. Our results and our efforts to eliminate the study limitations would suggest that the difference is driven by response to neo-adjuvant chemotherapy.

Thanks for listening, any questions? Acknowledgments: Endoscopists: Prof Aithal, Dr James. Surgeons: Mr Welch, Mr Catton, Mr Duffy. Pathologists: Dr Soomro, Dr Zaitoun, Dr Kaye.