Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma

Background: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy (NAC) in oesophageal adenocarcinoma (OAC). Methods: A questionnaire was distributed to 11 UK Upper GI cancer centres to determine the use of NAC response assessment. Records of consecutive patients undergoing oesophagogastric resection at 7 centres between January 2000 and December 2013 were reviewed. Pathological response to NAC was assessed using the Mandard tumour regression grade (TRG) and lymph node down-staging. Results: TRG (73%, n=8/11) was the most widely used system to assess response to NAC, but there was discordance on how TRG was used in practice. Of 1392 patients, 1293 had TRG assessment and data were available for clinical and pathological nodal staging (cN and pN) in 981 patients and TRG, cN and pN in 885 patients. There was a significant difference in survival between responders (TRG 1-2: median overall survival (OS) not reached) and non-responders (TRG 3-5: median OS: 2.2 years 95% CI: 1.936-2.505, p<0.0001; HR: 2.459 95% CI: 1.222-4.946, p=0.012). The presence of lymph node down-staging in local non-responders was associated with significantly improved OS (median not reached) versus those without lymph node down-staging (median OS: 1.919 yrs. 95 % CI: 1.681-2.158, p<0.0001). Conclusion: A clinically meaningful local response to neoadjuvant chemotherapy is restricted to the small minority of patients (15%) graded as TRG 1-2 only. In local non-responders a sub-set of patients (21%) derive benefit from NAC by lymph node down-staging and their survival mirrors that of local responders.