Pathologic Response And Survival Analysis Of Neoadjuvant Therapy For Rectal Cancer

Rectal cancer is one of common malignances with high incidence and mortality.Management for rectal cancer,especially for local advanced rectal cancer(cT3-4N0,or node-positive diseases),is still challenging for clinical practice.The current standard management for local advanced rectal cancer comprises neoadjuvant chemoradiotherapy followed by complete resection and adjuvant chemotherapy.The tumor response to neoadjuvant chemoradiotherapy is important for treatment efficacy evaluation and has been considered as an independent predictor of survival in patients with locally advanced rectal cancer.From radiobiological point of view,lymphocytes,as one of critical component of immune system,are known to be extremely radiosensitive,and there is a concern that radiotherapy-related lymphopenia may affect responses to immunotherapy.Also,benefits of postoperative chemotherapy for patients who received neoadjuvant chemoradiotherapy and surgical resection are equivocal,and estimates survival benefits of neoadjuvant chemoradiotherapy for patients with different tumor stages varies quite.This study aimed to investigate the association of circulating lymphocytes with tumor response during neoadjuvant chemoradiotherapy and prognosis,and to evaluate the survival benefits of neoadjuvant radiotherapy for rectal cancer.A prediction model for survival benefits of neoadjuvant radiotherapy was also established.Chapter 1.Association of circulating lymphocyte nadir with tumor response and survival in locally advanced rectal cancer after neoadjuvant chemoradiotherapyPurpose:Examine associations of absolute lymphocyte count(ALC)nadir during nCRT,pathologic response and prognosis for locally advanced rectal cancer(LARC).Materials and methods:Patients with LARC(cT3-4NO,or node-positive)treated between 2010 and 2015 with nCRT followed by complete resection were analyzed.The ALC value was obtained prior to,weekly dxuring the treatment,and one month after nCRT.Associations of ALC nadir with immune cells infiltrations,pathologic response and survival were analyzed.Results:A total of 102 patients were included in this analysis.Among them,24(23.5%)patients achieved pathologic complete response and 60(58.9%)patients achieved partial response respectively.Response rate was higher in high ALC nadir group than low nadir group(89.7%vs 67.6%,P=0.006).Compared to low ALC nadir group,increased tumor infiltrates of CD4+(4%vs 17.5%,P<0.001),CD8+(8%vs 30%,P<0.001)T cells and CD68+macrophages(6%vs 25%,P<0.001)were observed in high ALC nadir group.High ALC nadir[OR=4.32(95%CI,1.22-15.26),P=0,023]and well differentiation[OR=10.53(1.87-59.36),P=0.008]were associated with pathologic response.Patients with high ALC nadir yielded better DFS[HR=0.36(0.16-0.81),P=0.010]and OS[HR=0.24(0.08-0.69),P=0.004].Conclusions:Higher ALC nadir during nCRT is associated with a higher rate of pathologic response and better survival for LARC patients,suggesting that ALC may be a potential stratification strategy for LARC patients.Chapter 2.Overall survival in rectal cancer with neoadjuvant radiotherapy:A propensity-matched population-based studyPurpose:Compare sirvival outcomes of patients received neoadjuvant radiotherapy prior to surgical resection with stage-matched patients who proceeded directly to resection without neoadjuvant therapy,and to establish a prediction model for survival benefits of neoadjuvant radiotherapy.Materials and methods:This retrospective propensity score-matched cohort study identified patients with positive histology confirmation and received cancer-directed surgery with curative intent from the Surveillance,Epidemiology,and End Results database from 2004 through 2014.The primary endpoint overall survival was estimated by Kaplan-Meier methodology and was compared using the stratified log-rank test.Multivariate regression analysis was performed by using Cox proportional hazard model and inherent coefficients were used to produce a survival prediction model,implemented as nomograms.Receiver operation characteristic curve and calibration curve were used for discrimination and calibration validation.Results:26934 patients met the inclusion and were enrolled in this analysis.A total of 22008(11004 for each group)patients were identified in the propensity-match cohort.Among patients received adjuvant chemotherapy,there was no significant difference in comparison of overall survival between the group received surgical resection and that with neoadjuvant radiotherapy before resection,whether for stage?(mean overall survival time,without neoadjuvant radiotherapy 55.0 months,95%CI 53.4-56.6;with neoadjuvant radiotherapy 56.2 months,95%Cl 55.6-56.9;log-rank test P=0.467),stage ?(mean overall survival time,without neoadjuvant radiotherapy 55.1 months,95%Cl 54.3-55.9;with neoadjuvant radiotherapy 54.4 months,95%CI 53.9-54.9;log-rank test P=0.310),or stage ?(mean overall survival time,without neoadjuvant radiotherapy 52.1 months,95%CI 51.4-52.7;with neoadjuvant radiotherapy 52.3 months,95%CI 51.7-52.7;P=0.994).However,in case of receipt a prior combination therapy of neoadjuvant radiotherapy and surgical resection,patients who did not receive adjuvant chemotherapy yield worse overall survivals than those with postoperative chemotherapy,whether for stage ?(mean overall survival time,without neoadjuvant radiotherapy 49.1 months,95%Cl 44.5-53.8;with neoadjuvant radiotherapy 56.2 months,95%CI 55.6-56.9;log-rank test P<0.001),stage ?(mean overall survival time,without neoadjuvant radiotherapy 51.5 months,95%Cl 47.9-55.0;with neoadjuvant radiotherapy 54.4 months,95%CI 53.9-54,9;log-ralk test P=0.038,or stage ?(mean overall survival time,without neoadjuvant radiotherapy 47.5 months,95%CI 43.6-51.3;with neoadjuvant radiotherapy 52.3 months,95%CI 51.7-52.7;log-rank test P=0.014)diseases.Conclusion:Patients received neoadjuvant radiotherapy prior to surgical resection yield similar overall survival outcomes with stage-matched patients who proceed directly to resection without neoadjuvant therapy,in case of adjuvant chemotherapy is prescribed.Postoperative chemotherapy may be beneficial for rectal cancer patients with post-treatment stage ?-? diseases after neoadjuvant radiotherapy and surgical resection.