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Background: Patients (pts) affected with locally advanced rectal cancer (LARC) may respond differently to neoadjuvant chemoradiotherapy (nCRT). The identification of reliable biomarkers able to predict oncological outcomes could help in the development of risk-adapted treatment strategies. It has been suggested that inflammation parameters may have a role in predicting tumor response to nCRT and survival outcomes and in rectal cancer, but no definitive conclusion can be drawn at present. The aim of the current study is to evaluate the role of baseline inflammatory markers as prognostic and predictive factors in a large multicentric Italian cohort of LARC pts. Methods: Patients diagnosed with LARC from January 2002 to December 2019 in 9 Italian centers were retrospectively collected. Patients underwent long-course RT with chemotherapy based on fluoropyrimidine ± oxaliplatin followed by surgery. Inflammatory markers were retrieved based on a pre-treatment blood sample including HEI (hemo-eosinophils inflammation index), SII (systemic index of inflammation), NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio) and MLR (monocyte-to-lymphocyte ratio). Outcomes of interest were pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). Results: 808 pts were analyzed. pCR rate was 22 %, 5yOS and 5yDFS were 84.0% and 63.1% respectively. Multivariate analysis identified that a NLR cut-off value >1.2 and SII cut-off value >500 could predict pCR (p = 0.05 and 0.009 respectively). In addition to age, extramesorectal nodes and RT dose, MLR >0.18 (p = 0.03) and HEI = 3 (p = 0.05) were independent prognostic factors for DFS. Finally, age, RT dose, MLR with a cut-off >0.35 (p = 0.028) and HEI = 3 (p = 0.045) were independent predictors of OS. Conclusions: Higher values of baseline composite inflammatory markers can serve as predictors of lower pCR rates and worse survival outcomes in LARC patients undergoing nCRT. More reliable data from prospective studies could lead to the integration of these inexpensive and easy-to-derive tools into clinical practice.

Purpose: The aim of this study is to evaluate the long term survival of the addition of gefitinib to chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). Methods and materials: This previously published multicentre, open-label, phase I-II study, enrolled patients (pts) with LARC to receive CRT with concurrent 5-fluorouracil continuous intravenous infusion and a dose escalation of orally administered gefitinib, followed 6–8 weeks later by surgery. An intra-operative radiotherapy boost of 10 Gy was planned. Adjuvant chemotherapy was administrated in ypN1-2 pts. After a median f/u of >10 years, we analyzed Local Control (LC), Metastasis Free Survival (MFS), Disease Free Survival (DFS), Disease Specific Survival (DSS) and Overall Survival (OS). Predictive endpoints of clinical outcomes were tested by univariate and multivariate analysis. Variables analyzed included: age, gefitinib dose and interruptions, adjuvant CT, surgery type, ypT, ypN, and TRG grade. We have also analyzed late toxicity according to CTCAEv4. Results: Of the 41 initially enrolled pts, 39 were evaluable (27M, 12F). With a median f/u of 133 months, LC, MFS, DFS, OS and DSS at 5 years were 84%; 71%; 64%; 87% and 92%, respectively. The OS and DSS at 10 years were 61,5% and 76%, respectively. Grade 3-4 late toxicity occurred in 38% of pts: sexual (28,2%) and gastrointestinal toxicities (10,2%). Conclusion: Long term outcomes and late toxicity were similar to previously reported series. The addition of gefitinib did not improve outcomes in LARC. Gefitinib is not recommended for rectal cancer patients who received 5-FU based preoperative CRT. Further studies may identify if gefitinib is beneficial in selected group of patients. Keywords: Rectal cancer, Gefitinib, Log term follow-up, Chemoradiotherapy

Background: To retrospectively evaluate the difference in terms of pathologic complete response (pCR) according to time elapsed between chemoradiation (CRT) and total mesorectal excision (TME) on a large unselected real-life dataset of locally advanced rectal cancer (LARC) patients. Methods: A multicentre retrospective cohort study of LARC patients from 21 Italian Radiotherapy Institutions was performed. Patients were stratified into 3 different time intervals from CRT. The 1st group included 300 patients who underwent TME within 6 weeks, the 2nd 1598 patients (TME within 7–12 weeks) and the 3rd 196 patients (TME within 13 or more weeks after CRT), respectively. Results: Data on 2094 LARC patients treated between 1997 and 2016 were considered suitable for analysis. Overall, 578 patients had stage II while 1516 had stage III histological proven invasive rectal adenocarcinoma. A CRT schedule of one agent (N = 1585) or 2-drugs (N = 509) was administered. Overall, pCR was 22.3% (N = 468 patients). The proportion of patients achieving pCR with respect to time interval was, as follows: 12.6% (1st group), 23% (2nd group) and 31.1% (3rd group) (p 5040 cGy (p = 0.002) and longer interval (p 13 weeks) from CRT to surgery improves the pathological response (pCR and pathologic partial response; pPR) in comparison to historic data. Furthermore, radiotherapy dose >5040 cGy and two drugs chemotherapy correlated with pPR rate.