Residual Tumour Cell Density and the Relationship to Survival Following Pre-Operative Chemoradiation in Locally Advanced Rectal Cancer: Results of the NWCOG RICE Trial

Pre-operative chemoradiotherapy (CRT) is commonly used to downstage locally advanced rectal cancer (LARC). The degree of response is assessed using a number of subjective tumour regression grading systems. Tumour cell density (TCD) has been developed as an objective linear measure of response and may be more sensitive and reproducible.Patients with MRI-dened LARC received pre-operative CRT using a novel irinotecan-containing regimen, with surgery 9 weeks later. TCD analysis was performed on digitally scanned glass slides. TCD was measured in the pre-treatment biopsy (PTBTCD) and a representative slide from the resection specimen including a 9mm2 area of greatest TCD (GTCD) and the whole tumour area and/or scar TCD (WTTCD). A systematic sample of 300 random points were inserted into each area using virtual graticule software and manually assessed, TCD was expressed as the percentage of informative points falling on tumour cells. The work is presented on behalf of the NWCOG RICE trial investigators and was part-funded by a PathSoc fellowship. 142 patients commenced CRT and 135 underwent surgery. Median TCD for PTBTCD, GTCD and WTTCD was 38.7%, 7.8% and 1.7% respectively. The number (%) of patients with a TCD of 0% was 0 (0%), 30 (23.6%) and 36 (28.3%) respectively. Distribution of TCD was normal in PTBTCD but highly positively skewed post-resection. Low PTBTCD (split by the median) predicted better 3-year disease free survival (DFS; 76% vs. 60%, p=0.05) although not overall survival (OS; p=0.47). Low WTTCD predicted better DFS and OS (DFS 71% vs. 58%, p=0.05; OS 90% vs. 77%, p=0.02) although no dierence was seen for GTCD (p=0.26; p=0.26). Pre-operative CRT markedly reduces TCD in LARC, and provides a continuous measure to compare dierent regimens. In the pre-treatment biopsy, lower TCD may predict improved DFS. Following resection, TCD across the whole tumour and scar more accurately predicts DFS and OS than using a selected area of greatest TCD.