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Pathological primary tumour and lymph node regression following neoadjuvant chemotherapy in resectable oesophagogastric cancer: Pooled analysis of 1619 patients from two randomised trials
Background
No definitive largescale data exists evaluating the role of pathologically defined regression changes within lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy. There is also a lack of centralised data assessing the relationship between tumour and LN regression changes and their impact on survival in localised OG cancer.
Methods
Data and samples from two large prospective randomised trials in resectable OG adenocarcinoma (UK MRC OE05 and ST03 trials) were pooled using a two-stage meta-analysis. H&E stained slides were available for central review from 1619 patients who underwent surgical resection following neoadjuvant chemotherapy. Mandard tumour regression grade (TRG) and LN regression ((LNR) scored as present/absent) were assessed centrally and correlated with survival using a Cox model to obtain hazard ratios. An exploratory analysis to assess whether the available results could define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis.
Results
19,489 H&E slides from 761 OE05 participants and 20,277 slides from 858 ST03 participants were reviewed centrally. Within ST03, there was no difference between treatment arm (ECX ± Bev) in terms of TRG score or LNR. Within OE05, ECX was associated with lower TRG score and higher rates of LNR than CF. Neither trial demonstrated a correlation between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG score, lower pathological N-stage (pN), lower pathological T-stage (pT), the presence of LNR, a well/moderately differentiated tumour, and achieving an R0 resection were all associated with significantly increased survival. However, multivariable analysis found that only pN, pT, differentiation and R0 were independent indicators of prognosis. Importantly, pN stage at resection significantly improved survival (3-year OS for ypN0 74% vs 36% for ypN1+, HR 3.4, p Exploratory CART analysis identified six subgroups based on the prognostic variables above, with 3-year OS ranging from 83% to 22%; with the most important single prognostic variable being pathological N-stage.
Conclusions
This study represents the largest central review of primary tumour and LN regression in early OG cancer from patients treated with neoadjuvant chemotherapy within randomised controlled trials. pN and pT stage, tumour differentiation, and resection status in the post-operative specimen are strong independent indicators of survival in multivariate analysis. Exploratory CART analysis can be used to define groups with differing prognoses. Our results suggest that the assessment of LNR and TRG is not necessary to define prognosis further.
Legal entity responsible for the study
The authors.
Funding
This study represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London.
Disclosures
N. Starling: Honoraria (self): Eli Lilly, GSK, Clinical Options, Merck Serono, Servier, Amgen, Lilly Bangladesh, MSD Oncology, Pierre Fabre, Lilly Thailand; Advisory / Consultancy: Pfizer, AstraZeneca, GSK, Servier, Novartis, MSD (Merck), MSD Oncology; Research grant / Funding (self): AstraZeneca, NIHR EME, RM/ICR BRC, Pfizer, RMCC, BMS, Merck; Travel / Accommodation / Expenses: Merck, AstraZeneca, MSD Oncology, BMS, Roche, Eli Lilly, GI ASCO. I. Chau: Honoraria (self): Eli-Lilly, Servier, Eisai; Advisory / Consultancy: Eli-Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, Eisai, Daiichi-Sankyo; Research grant / Funding (institution): Janssen-Cilag, Eli-Lilly. D. Cunningham: Research grant / Funding (institution): MedImmune / AZ, Celgene, Bayer, 4SC, Eli Lilly, Clovis, Roche. All other authors have declared no conflicts of interest.
