Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer

Aim Current management of locally advanced rectal cancer includes neoadjuvant chemoradiation in selected patients to increase the chance of a tumour‐free circumferential resection margin. There is uncertainty over the role of and selection criteria for additional systemic therapy in this group of patients. In this retrospective study we investigate the association between markers of systemic inflammatory response (SIR) and outcome from treatment. Method One hundred and fifteen patients with locally advanced rectal cancer undergoing preoperative chemoradiation had recording of full blood count parameters including neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratios (PLR). Postoperative surgical margins (R status) and pathological stage were documented. Outcome measures were overall survival (OS), time to local recurrence (TTLR) and disease‐free survival (DFS). Cox regression analysis was performed to identify predictors of outcome. Results Only NLR and R status were significant predictors for all outcome measures on univariate and multivariate analysis. Elevated NLR (≥ 5) was associated with decreased OS, [hazard ratio (HR) and 95% CI, 7.0 (2.6–19.2)], decreased TTLR [HR 3.8 (1.3–11.2)] and shorter DFS [HR 4.1 (1.7–9.8)]. Median survival for patients with an elevated NLR was 18.8 months compared with 54.4 months without an elevated NLR (P < 0.001). Conclusion In addition to postoperative R‐status, an elevated NLR is also a valuable prognostic marker in patients undergoing chemoradiation for locally advanced rectal carcinoma. It is associated with worse OS, TTLR and DFS. An elevated NLR may be a useful additional tool in guiding the decision‐making process for adjuvant or neoadjuvant therapies.     

Response to neoadjuvant therapy for rectal cancer: influence on long-term results

OBJECTIVE: Pre-operative treatment with chemoradiotherapy (CRT) seems to improve local control and overall survival in patients with rectal cancer. The aims of the study were to analyse the impact on overall, disease free and cancer related survival of tumour response to pre-operative CRT and to analyse the influence of the degree of response on long-terms results. PATIENTS AND METHODS: Patients with a locally advanced rectal cancer, treated by pre-operative CRT were studied. A radical resection of the rectal tumour with mesorectal excision was performed within 6-8 weeks. Judged on the final TNM classification patients were considered responders when the tumour showed histologically a complete response, microscopic residual disease or a partial response. Non-responders were those in whom the extent of disease remained stable or progressed. Results Radical excision was performed in 103 patients, and a palliative resection in five. Forty-three patients underwent abdominoperineal resection and 65 anterior resection of the rectum. Seventy-one (65.7%) patients showed a response to CRT, while 37 (34.3%) did not. The overall local and distant recurrence rates were 6.8% and 21.3%. Tumour recurrence (P < 0.008) and disease free survival (P < 0.007) were significantly different in responders and nonresponders. Of the 71 responders, 16 had a pathological complete response, 27 had persisting microscopic disease and 28 had macroscopic residual disease. No differences in cancer specific outcome were observed in these groups. CONCLUSION: Pathological response to pre-operative CRT is associated with improved tumour recurrence and disease-free survival rates. Any response to pre-operative CRT appears to improve outcomes as much as a complete response.     

CEA水平与进展期直肠癌新辅助放化疗疗效的关系

目的探讨癌胚抗原在预测进展期直肠癌对术前新辅助放化疗反应中的作用。方法对我院接受术前新辅助放化疗的48例进展期直肠癌分组,按照治疗前CEA的水平分为CEA升高组和CEA正常组,对切除术后标本进行分析,比较两组病例在肿瘤局部降期及肿瘤消退方面的差异。结果CEA升高组共21例,其中术后肿瘤降期（包括术后病理ypT02有12例,57％）,出现肿瘤消退（包括TGR2~4者11例,52％）CEA正常组共27例,其中术后肿瘤降期（包括术后病理ypT02有20例,74％）,出现肿瘤消退（包括TGR2~4者21例,78％）。CEA升高组肿瘤降期及消退比率均低于CEA正常组。结论治疗前CEA水平的升高可能预示直肠癌对术前新辅助放化疗的反应性差,有助于直肠癌患者个体化治疗方案的选择。     

Accuracy of endorectal ultrasonography in staging locally advanced rectal cancer after preoperative chemoradiation

Aim  The aim of our study was to determine the accuracy of endorectal ultrasonography (ERUS) in staging locally advanced rectal cancer after preoperative neoadjuvant chemoradiation and to point out the most common reasons for false interpretation. Methods  Forty-four patients with locally advanced rectal cancer received neoadjuvant chemoradiation followed by radical surgery. Restaging was done 1–2 weeks before surgery and the results of ERUS staging were compared with histopathology findings of the resected specimen. Results  The accuracy of ERUS for T stage after chemoradiation was 75% (33/44). Overstaging occurred in 18% (8/44) of patients, and 7% (3/44) were understaged. The majority of overstaging occurred in patients with ERUS T3 tumors, eventually found to have pathological pT0–pT2 staging. Five patients (11.4%) had complete histology regression and only one of these patients was staged correctly while others were overstaged. In the detection of perirectal lymph node metastases, ERUS was accurate in 68% of patients (30/44). Twenty percent (9/44) of patients were overstaged and 11% were (5/44) understaged. Conclusions  ERUS provides a good accuracy rate for staging rectal cancer after neoadjuvant chemoradiation. However, it is insuficient in detection of complete pathological response.     

Accuracy of endorectal ultrasound after preoperative radiochemotherapy in locally advanced rectal cancer

Objectives: Factors limiting the accuracy of endorectal ultrasound in staging, locally advanced primary rectal cancer after preoperative neoadjuvant radiochemotherapy (RCT) were evaluated. Methods: Patients (n= 84) with initial locally advanced rectal cancer (uT3/uT4) undergoing R0 resection were investigated after preoperative treatment that combined radiotherapy up to 45 Gy with two cycles of chemotherapy (5-FU and leucovorin on d 1–5 and 22–28). At 4 to 6 weeks after completion of RCT and before tumor resection, preoperative endoluminal ultrasound was performed. Results: The accuracy to predict the depth of tumor infiltration (T-category) was found to correlate with downstaging. The T-category was correctly staged before surgery in 15 of the 51 responders (29%) and in 27 of 33 nonresponders (82%), whereas misinterpretation occurred in 36 of the responders (71%) and in 6 of the nonresponders (18%) (p < 0.001). Neither tumor distance from anal verge nor tumor location correlated with the staging accuracy. Lymph node involvement was correctly assessed in 48 patients (57%). Wall invasion was correctly ascertained in 42 patients (50%), with under estimation in 11 patients (13%) and overestimation in 31 patients (37%). Conclusions: After radiochemotherapy, endosonography does not provide a satisfactory accuracy for preoperative staging of rectal cancer. New interpretation and diagnostic criteria are needed for the prediction of treatment response. Received: 28 February 1999/Accepted: 2 April 1999     

直肠癌术前放化疗反应相关的分子标志物分析

目的 探讨与进展期直肠癌术前放化疗反应相关的分子标志物.方法 分析我院2005年1月至2012年12月间92例直肠癌接受术前放化疗后行根治性手术石蜡包埋肿瘤组织,检测与直肠癌相关的分子生物学指标癌胚抗原（CEA）、p53、血管生长因子（VEGF）、Ki-67及胸苷酸合成酶（TS）,分析其对直肠癌术前放化疗反应的影响.结果 与直肠癌术前放化疗反应相关因素中,CEA、p53、VEGF和TS高表达与术前放化疗反应差明显相关（P＜0.05）.结论 通过对直肠癌术前放化疗影响因素的分析,可预测患者对放化疗的反应,指导临床进行个体化治疗及相关干预.     

Complete clinical response to neoadjuvant chemoradiotherapy in patients with rectal cancer: opinions of British and Irish specialists

Introduction Advances in neoadjuvant treatment have highlighted the phenomenon of complete clinical response (CCR) in a proportion of patients with rectal cancer. Radical surgery may be associated with a poor functional outcome and quality of life and has a small but significant risk of mortality. This study aimed to assess opinion of colorectal surgeons on issues surrounding the question of nonoperative management in patients who demonstrate complete response after neoadjuvant therapy. Method A questionnaire was sent to members of the Association of Coloproctology of Great Britain and Ireland regarding investigations, clinical management, pathological assessment and oncological outcome in rectal cancer patients with a complete response to neoadjuvant chemoradiotherapy. Results A total of 122 consultants responded (26% response rate). Most surgeons (58%) would not consider conservative management of patients with a complete response and even more (69%) expressed that they would never discuss nonoperative management in patients with rectal cancer who are fit for curative surgery. Over 70 different combinations of investigations and imaging modalities were suggested to define a CCR. Eighty‐six per cent of consultants felt that a pathology report stating no evidence of residual adenocarcinoma did not rule out the presence of tumour cells and all respondents estimated the percentage of patients with pathological complete response as < 20%. Conclusions No consensus exists as to what defines a complete response and at present there is resistance to offering nonoperative management in selected patients. With improvements in neoadjuvant treatment modalities, it will be increasingly important to consider nonoperative management in the future.     

直肠癌新辅助放化疗后病理完全缓解的相关研究进展

局部晚期直肠癌标准的治疗方案为术前新辅助放化疗加手术的综合治疗。研究显示,直肠癌患者术前放化疗后达病理完全缓解者预后较好。尽管对这些患者的后续治疗方案有较大分歧,但已倾向于保守治疗而非根治性手术治疗。本文就局部晚期直肠癌术前新辅助放化疗后病理完全缓解的预后及预测等相关研究进展作一简要综述。     

Long-term results of preoperative chemoradiation for distal rectal cancer correlation between final stage and survival

Neoadjuvant chemoradiation treatment (CRT) has resulted in significant tumor downstaging and improved local disease control for distal rectal cancer. The purpose of the present study was to determine the correlation between final stage and survival in these patients regardless of initial disease stage. Two hundred sixty patients with distal (0-7 cm from anal verge) rectal adenocarcinoma considered resectable were treated by neoadjuvant CRT with 5-FU and leucovorin plus 5040 cGy. Patients with incomplete clinical response 8 weeks after CRT completion were treated by radical surgical resection. Patients with complete clinical response were managed by observation alone. Overall survival and diseasefree survival were compared according to Kaplan-Meier curves and log-rank tests according to final stage. Seventy-one patients (28%) showed complete clinical response (clinical stage 0). One hundred sixtynine patients showed incomplete clinical response and were treated with surgery. In 22 of these patients (9%), pathologic examination revealed pT0 N0 M0 (stage p0), 59 patients (22%) had stage I, 68 patients (26%) had stage II, and 40 patients (15%) had stage III disease. Overall survival rates were significantly higher in stage c0 (P = 0.01) compared with stage p0. Disease-free survival rate showed better results in stage c0, but the results were not significant. Five-year overall and disease-free survival rates were 97.7% and 84% (stage 0); 94% and 74% (stage I); 83% and 50% (stage II); and 56% and 28% (stage III), respectively. Cancer-related overall and disease-free survival may be correlated to final pathologic staging following neoadjuvant CRT for distal rectal cancer. Also, stage 0 is significantly associated with improved outcome. Presented at the Forty-Fifth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, Louisiana, May 15–19, 2004 (oral presentation).     

Adjuvant vs. neoadjuvant radiochemotherapy for locally advanced rectal cancer: the German trial CAO/ARO/AIO-94

Aim The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy (RCT) is recommended for advanced disease (pT3/4 or pN+). In recent years, encouraging results of pre‐operative radiotherapy have been reported. This prospective randomized phase‐III‐trial (CAO/ARO/AIO‐94) compares the efficacy of neoadjuvant RCT to standard postoperative RCT. We report on the design of the study and first results with regard to toxicity of RCT and postoperative morbidity. Patients and methods Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre or postoperative RCT: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumour and the pelvic lymph nodes. 5‐FU (1000 mg/m²/d) was administered concomitantly in the 1th and 5th week of radiation as 120 h‐continuous infusion. Four additional cycles of 5‐FU‐chemotherapy (500 mg/m²/d, i.v.‐bolus) were applied. RCT was identical in both arms except for a small‐volume boost of 5.4 Gy postoperatively. The time interval between RCT and surgery was 4–6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. Primary endpoints of the study are 5‐year survival and local and distant control. Secondary endpoints include the rate of curative (R0) resection and sphincter saving procedures, toxicity of RCT, surgical complications and quality of life. Results As of July 2002, 805 patients were randomized from 26 participating institutions. Acute toxicity (WHO) of RCT was low, with less than 15% of patients experiencing grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative RCT‐arm and 11% in the pre‐operative RCT‐arm having grade 3‐, and 1% in either arm having grade 4‐diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postop. RCT) and 12% (pre‐op. RCT) of patients, respectively, suffering from anastomotic leakage, 3% (postop. RCT) and 3% (pre‐op. RCT) from postoperative bleeding, and 6% (postop. RCT) and 4% (pre‐op. RCT) from delayed wound healing. Conclusion The patient accrual to the trial is satisfactory. Neoadjuvant RCT is well tolerated and bears no higher risk for postoperative morbidity.