Lymph node ratio is an independent prognostic factor in patients with rectal cancer treated with preoperative chemoradiotherapy and curative resection

Purpose

To evaluate the prognostic effect of lymph node ratio (LNR) in patients with locally advanced rectal cancer who were treated with curative resection after preoperative chemoradiotherapy (CRT).

Methods

Between October 2001 and December 2007, 519 patients who had undergone curative resection of primary rectal cancer after preoperative CRT were enrolled. Of these, 154 patients were positive for lymph node (LN) metastasis and were divided into three groups according to the LNR (≤0.15 [n = 80], 0.16–0.3 [n = 44], >0.3 [n = 30]) to evaluate the prognostic effect on overall survival (OS) and disease-free survival (DFS).

Results

LNR (≤0.15, 0.16–0.3, and >0.3) was significantly associated with 5-year OS (90.3%, 75.1%, and 45.1%; p < 0.001) and DFS (66.7%, 55.8%, and 21.9%; p < 0.001) rates. In a multivariate analysis, LNR (≤0.15, 0.16–0.3, and >0.3) was a significant independent prognostic factor for OS (hazard ratios [HRs], 1, 3.609, and 8.197; p < 0.001) and DFS (HRs, 1, 1.699, and 3.960; p < 0.001). LNR had a prognostic impact on OS and DFS in patients with <12 harvested LNs, as well as in those with ≥12 harvested LNs (p < 0.05).

Conclusion

LNR was a significant independent prognostic predictor for OS and DFS in patients with locally advanced rectal cancer who were treated with curative resection after preoperative CRT.     

Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: A near pathologic complete response does not translate into good clinical outcome

Background

After preoperative chemoradiotherapy (CRT) for rectal cancer, clinically undetectable residual tumour deposits or pathologic lymph nodes may remain in the mesorectum.

Aim

The aim of this study was to report histopathological effects of CRT and factors affecting outcome in a uniformly treated series of locally advanced rectal cancer (LARC) patients.

Methods

Between 2004 and 2008, 107 patients with cT3 (threatening the mesorectal fascia or <5 cm from the anal verge), cT4 or cN2 rectal cancer were treated with preoperative CRT (25 × 2 Gy with capecitabine) and TME 6–8 weeks later. Central histopathological review followed. Tumour regression grade (TRG) was scored in pCR, near-pCR, response and no response. Cox regression was performed to identify prognosticators.

Results

The 3-year distant metastasis-free interval, disease-free rate and overall survival rate were 82%, 73% and 87% (median 44 months follow-up). TRG consisted of 20% pCR, 11% near-pCR, 55% response and 14% no response. 6/21 pCR patients harboured nodal metastases. 5/12 near-pCR had ypT3 disease, while 6 harboured node metastases. 5/12 near-PCR patients developed distant metastases. ypN and TRG were powerful outcome discriminators.

Conclusion

The high number of near-pCR with ypT3 or ypN1/2 and their poor outcome demonstrates that “watch-and-wait” in LARC patients should be applied with care.     

Defining and predicting early recurrence in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy

BackgroundThe definition of “early recurrence (ER)” after rectal cancer surgery is currently unclear.ObjectiveTo determine an evidence-based cut-off to distinguish early and late recurrence (LR) for patients with rectal cancer and compare the clinicopathological factors between the two groups.MethodsPatients who underwent neoadjuvant chemoradiotherapy (nCRT) and radical resection for locally advanced rectal cancer were included. A minimum p-value approach was used to evaluate the optimal cut-off value of recurrence-free survival to divide the patients into ER and LR groups based on overall survival. A logistic regression model was used to assess risk factors for ER.ResultsA total of 763 patients were included, of which 167 (21.9%) experienced recurrence. The optimal cut-off value of recurrence-free survival to differentiate between ER (n = 125, 74.9%) and LR (n = 42, 25.1%) was 24 months (P = 0.000001). The median postrecurrence survival of ER and LR was 12 months and 22 months, respectively (p = 0.028). The most common recurrent sites in patients with ER and LR were lung metastases, the incidence of liver metastases, however, differed considerably in ER and LR (27.2% vs 9.5%, P = 0.019). Risk factors including elevated preoperative carcinoembryonic antigen (CEA), higher ypTNM stage, positive circumferential resection margin (CRM), and perineural invasion were significantly associated with ER.ConclusionA recurrence-free interval of 24 months is the optimal cut-off value for defining ER versus LR. Elevated preoperative CEA, higher ypTNM staging, positive CRM, and perineural invasion were associated with ER of locally advanced rectal cancer.     

Lymph node yield in rectal cancer surgery: Effect of preoperative chemoradiotherapy

Aim

Adequate lymph node resection in rectal cancer is important for staging and local control. This study aims to verify the effect of neoadjuvant chemoradiation, as well as some clinicopathological features, on the yield of lymph nodes in rectal carcinoma.

Methods

Data on consecutive patients who had total mesorectal excision for rectal adenocarcinoma at a single cancer center between January 2003 and July 2008 were reviewed. No patient had any prior pelvic surgery or radiotherapy. Patients had neoadjuvant chemoradiotherapy if they were stage II or III.

Results

A total of 116 patients were included. The mean age was 53 years (range 29–83). Fifty-nine patients (51%) received neoadjuvant therapy before resection. The mean number of lymph nodes removed was 18 (range 4–67) per specimen. There was less lymph node yield in patients who received neoadjuvant therapy (16 vs. 19, p = 0.008). Only 64% of patients who had preoperative therapy had 12 lymph nodes or more in the specimen as opposed to 88% of those who had surgery upfront (p = 0.003). Other factors associated with lower lymph node yield included: female sex (p = 0.03) and tumour location in the lower rectum (p = 0.002). Age, tumour stage and grade, type of operation and surgical delay did not affect the number of lymph nodes removed.

Conclusion

Preoperative chemoradiotherapy for rectal cancer results in reduction in lymph node yield. Female sex and lower rectal tumours are also associated with retrieval of fewer lymph nodes.     

Individualized conditional survival nomograms for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy and radical surgery

BackgroundConditional survival (CS) considers the time already survived after surgery when estimating the survival probability, which may provide further useful prognostic information.ObjectiveTo evaluate CS in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) and to create CS nomograms predicting the conditional probability of survival after proctectomy.MethodsConsecutive patients with LARC who received nCRT followed by radical resection between 2011 and 2016 were identified. CS was defined as the probability of surviving y years after already surviving for x years. The formula used for CS was CS(x|y) = S(x + y)/S(x), where S(x) represents the survival at x years. Nomograms were constructed to predict the 5-year conditional overall survival (cOS) and conditional recurrence-free survival (cRFS).ResultsA total of 785 patients were included. The median follow-up time was 65.5 months. The probability of achieving 5-year survival after surgery for cancer increases with additional survival time. Maximum tumor diameter, distance from the anal verge, preoperative CA19-9 level, ypTNM stage and perineural invasion were independent predictors of OS, while maximum tumor diameter, distance from the anal verge, ypTNM stage and perineural invasion were independent risk factors for RFS. The nomograms predicted 5-year cOS and cRFS using these predictors and the time already survived. The online calculator can be accessed at http://www.rectalcancer.top/webcalculator.ConclusionThe proposed nomograms predict survival in patients after surgery, taking the time already survived into account.     

Neoadjuvant chemoradiotherapy for locally advanced rectal cancer: The debate continues

Rectal carcinoma represents the 30% of all colorectal cancers, with about 40000 new cases/years. In the past two decades, the management of rectal cancer has made important progress, highlighting the main role of a multimodality strategy approach, combining surgery, radiation therapy and chemotherapy. Nowadays, surgery remains the primary treatment and neo-adjuvant chemoradiotherapy, based on fluoropyrimidine (5-FU) continuous infusion, is considered the standard in locally advanced rectal carcinoma. The aim is to reduce the incidence of local recurrence and to perform a conservative surgery. To improve these purposes different drugs combination have been tested in the neo-adjuvant setting. At American Society of Clinical Oncology 2014 an important abstract was presented focusing on the role of adding oxaliplatin to concomitant treatment, in patients with locally advanced rectal carcinoma. Rodel et al reported on the CAO/ARO/AIO-04 randomized phase III trial that compared standard treatment with 5-FU and radiation therapy, to oxaliplatin plus 5-FU in association with radiation therapy. The addition of oxaliplatin to the neo-adjuvant treatment has been shown to improve disease-free survival from 71.2% to 75.9% (P = 0.03). This editorial was planned to clarify the optimal treatment in patients with locally advanced rectal cancer, considering the results from CAO/ARO/AIO-04 study.     

同期放化疗治疗局部晚期不可手术的直肠癌近期疗效观察

目的：观察同期放化疗治疗局部晚期不可手术的直肠癌患者的近期疗效及耐受性。方法：３８例经病理证实的局部晚期或局部 区域复发的直肠癌患者接受全盆腔三维适形放疗ＤＴ４６～５０Ｇｙ／２３～２５ｆ,后缩野至肿瘤区继续推量至ＤＴ６４～６６Ｇｙ／３２～３３ｆ,同期接受奥沙利铂１３０ｍｇ／ｍ^２ｄ_１,氟尿嘧啶３５０ｍｇ／ｍ^２ｄ_１～ｄ_５,甲酰四氢叶酸２００ｍｇ／ｍ^２ｄ_１～ｄ_５,４周为１周期,共２个周期。结果：获ＣＲ７例（１９.４％）,ＰＲ１６例（４４.４％）,ＳＤ６例（１６.７％）,ＰＤ７例（１９.４％）,总有效率（ＣＲ＋ＰＲ）为６３.９％;疼痛症状缓解率为１００％;全身状况好转率７２.２％;中位生存时间为２２个月,１年和２年总生存率分别为６７.７％和２１.３％。治疗相关的毒副反应以中性粒细胞减少、腹泻、恶心呕吐以及周围神经毒性反应为主,其３级毒副反应的发生率分别为１９.４％、１６.７％、１３.９％和１１.１％,均无３级以上毒副反应发生。结论：以奥沙利铂为基础的化疗同期联合放疗对局部晚期不可手术直肠癌患者具有较好的姑息治疗作用,其治疗依从性高,治疗相关毒性可以接受,值得临床进一步推广。     

靶向治疗联合新辅助放化疗在局部进展期直肠癌中的应用

目前新辅助放化疗联合全直肠系膜切除术（TME）是局部进展期直肠癌（LARC）的标准治疗模式.靶向药物在LARC新辅助治疗中耐受性及安全性良好,但与常规新辅助放化疗相比较,病理完全缓解（pCR）率并无提高,仍需大样本随机对照研究证实其在LARC新辅助治疗中的作用.     

Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy

PURPOSE: To evaluate expression of a panel of molecular markers, including p53, p21, MLH1, MSH2, MIB-1, thymidylate synthase, epidermal growth factor receptor (EGFR), and tissue vascular endothelial growth factor (VEGF), before and after treatment in patients treated with neoadjuvant chemoradiotherapy for locally advanced rectal cancer, to correlate the constitutive profile and dynamics of expression with pathologic response and outcome. METHODS AND MATERIALS: Expression of biomarkers was evaluated by immunohistochemistry in tumor samples from 91 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy (50 Gy) plus concurrent 5-fluorouracil by continuous intravenous infusion. RESULTS: A pathologic complete remission was observed in 14 patients (15.4%). Patients with MLH1-positive tumors had a higher pathologic complete response rate (24.3% vs. 9.4%; p = 0.055). Low expression of constitutive p21, absence of EGFR expression after chemoradiotherapy, and high Dworak's tumor regression grade (TRG) were significantly associated with improved disease-free survival and overall survival. A high MIB-1 value after chemoradiotherapy was significantly associated with worse overall survival. Multivariate analysis confirmed the prognostic value of constitutive p21 expression as well as EGFR expression and MIB-1 value after chemoradiotherapy among patients not achieving TRG 3-4. CONCLUSIONS: In our study, we observed the independent prognostic value of EGFR expression after chemoradiotherapy on disease-free survival. Moreover, our study suggests that a constitutive high p21 expression and a high MIB-1 value after neoadjuvant chemoradiotherapy treatment could predict worse outcome in locally advanced rectal cancer.     

直肠癌新辅助治疗后病理降期相关研究进展

术前同步放化疗已成为局部晚期直肠癌的标准治疗模式.新辅助治疗后病理降期与直肠癌预后关系密切,找到能预测直肠癌新辅助治疗病理降期标记,有着重要的临床意义.不同放化疗方案、靶向药物在新辅助治疗中的应用、新辅助治疗后至手术间隔时间与病理降期相关.     

Predictors of pathologic complete response in patients with residual flat mucosal lesions after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

ObjectiveThe accurate prediction of tumor response to neoadjuvant chemoradiotherapy (nCRT) remains challenging. Few studies have investigated pathologic complete response (ypCR) prediction in patients with residual flat mucosal lesions after treatment. This study aimed to identify variables for predicting ypCR in patients with residual flat mucosal lesions after nCRT for locally advanced rectal cancer (LARC).MethodsData of patients with residual flat mucosal lesions after nCRT who underwent radical resection between 2009 and 2015 were retrospectively collected from the LARC database at Peking University Cancer Hospital. Univariate and multivariate analyses of the association between clinicopathological factors and ypCR were performed, and a nomogram was constructed by incorporating the significant predictors.ResultsOf the 246 patients with residual flat mucosal lesions included in the final analysis, 56 (22.8%) had ypCR. Univariate and multivariate analyses showed that pretreatment cT stage (pre-cT) ≤T2 (P=0.016), magnetic resonance tumor regression grade (MR-TRG) 1−3 (P=0.001) and residual mucosal lesion depth =0 mm (P<0.001) were associated with a higher rate of ypCR. A nomogram was developed with a concordance index (C-index) of 0.759 and the calibration curve showed that the nomogram model had good predictive consistency. The follow-up time ranged from 3.0 to 113.3 months, with a median follow-up time of 63.77 months. The multivariate Cox regression model showed that the four variables in the nomogram model were not risk factors for disease-free survival (DFS) or overall survival (OS).ConclusionsCompletely flat mucosa, early cT stage and good MR-TRG were predictive factors for ypCR instead of DFS or OS in patients with LARC with residual flat mucosal lesions after nCRT. Endoscopic mucosal re-evaluation before surgery is important, as it may contribute to decision-making and facilitate nonoperative management or organ preservation.     

Inferior mesenteric artery lymph node metastasis in rectal cancer treated with neoadjuvant chemoradiotherapy: Incidence,prediction and prognostic impact

Aim

To assess the effect of neoadjuvant chemoradiotherapy (nCRT) on inferior mesenteric artery (IMA) nodal metastasis and identify predictors for IMA nodal metastasis in locally advanced rectal cancer (LARC) after nCRT.

Oncologic benefit of adjuvant chemotherapy for locally advanced rectal cancer after neoadjuvant chemoradiotherapy and curative surgery with selective lateral pelvic lymph node dissection: An international retrospective cohort study

IntroductionIntensive local treatment comprising total mesorectal excision (TME) with selective lateral pelvic lymph node dissection (LPND) after neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) has received attention among clinicians treating rectal cancer. It remains unclear whether adjuvant chemotherapy (ACT) after intensive local treatment is beneficial for these patients. We evaluated the oncologic benefit of ACT for patients with LARC who received intensive local treatment.Materials and methodsThis international multicentre retrospective cohort study included 737 patients treated in Japan and Korea between 2010 and 2017. The effectiveness of ACT on recurrence-free survival (RFS) was evaluated using univariable and multivariable Cox proportional hazards models, with subgroup analyses to identify subpopulations potentially benefiting from ACT.ResultsThe median follow-up was 49 months; the 5-year RFS and local recurrence rates for the entire cohort were 72.1% and 4.9%, respectively; 514 patients (69.7%) received adjuvant chemotherapy, without an oncologic benefit (hazard ratio, 1.14; 95% confidence interval [CI]: 0.79–1.68) demonstrated in the multivariable Cox regression analysis. In subgroup analyses, the distributions of the 95% CI in patients aged ≥70 years and those with ypStage 0 tended to place a disproportionate emphasis that favoured the non-ACT treatment strategy.ConclusionDespite achieving good local control with intensive local treatment strategy, the effectiveness of ACT for the LARC patients with CRT followed by TME with selective LPND was not proved. Elderly patients and those with ypStage0 may not receive benefit from ACT after CRT and TME ± LPND.     

Lymph node yield after rectal resection in patients treated with neoadjuvant radiation for rectal cancer: A systematic review and meta-analysis

BackgroundThe lymph node status represents a major prognostic factor in colorectal cancer. However, it was demonstrated that neoadjuvant chemoradiotherapy (CRT) decreases the numbers of lymph nodes in the specimen. Several studies describe less than 12 lymph nodes in the resected specimen of rectal cancer patients after neoadjuvant radiation. This meta-analysis quantifies the influence of neoadjuvant CRT or radiotherapy (RT) only on the lymph node yield in rectal cancer patients.MethodsWe performed a systematic review and searched PubMed, EMBASE and the Cochrane Library without any language restriction from 1st of January 1980 until 31st March 2015. Two reviewers examined all publications independently and extracted the relevant data if the study assessed lymph node counts or positive lymph node yields of patients who received neoadjuvant treatment compared with patients who did not receive neoadjuvant treatment. Meta-analyses were conducted to quantify the mean difference in lymph node yield.ResultsA total of 34 articles (including 37 datasets) were included in the meta-analyses. Neoadjuvant CRT resulted in a mean reduction of 3.9 lymph nodes (95% confidence interval [CI] 3.7–4.1) and an average reduction in harvested positive lymph nodes of 0.7 (95% CI 0.2–1.2) compared with patients who received no neoadjuvant therapy. Individuals who received neoadjuvant RT had, in average, 2.1 lymph node less (95% CI 1.7–2.5) resected compared with their counterparts who received no neoadjuvant treatment.ConclusionsNeoadjuvant CRT or RT only in rectal cancer patients leads to a decrease in lymph node harvest of approximately four and two lymph nodes, respectively. We therefore stress the importance of intensifying all efforts from involved subspecialities (i.e. surgeons and pathologists) to reach the benchmark harvest of 12 resected lymph nodes according to current guidelines.     

Predictive factors for early distant metastasis after neoadjuvant chemoradiotherapy in locally advanced rectal cancer

BACKGROUNDDistant relapse is the leading cause of cancer-related death in locally advanced rectal cancer. Neoadjuvant chemoradiation (NACRT) followed by surgery inevitably delays delivery of systemic treatment. Some patients show early distant metastasis before systemic treatment.AIMTo identify the most effective treatments. We investigated prognostic factors for distant metastasis, especially early distant metastasis, using the standard treatment paradigm to identify the most effective treatments according to recurrence risk.METHODSFrom January 2015 through December 2019, rectal cancer patients who underwent NACRT for having clinical T 3-4 or clinical N 1-2 disease according to the 8^th American Joint Committee on Cancer staging system were included. Radiotherapy was delivered to the whole pelvis with concomitant chemotherapy. Patients received surgery 6-8 wk after completion of NACRT. Adjuvant chemotherapy was administered at the physician’s discretion. RESULTSA total of 127 patients received NACRT. Ninety-three patients (73.2%) underwent surgery. The R0 resection rate was 89.2% in all patients. Pathologic tumor and node downstaging rates were 41.9% and 76.3%. Half the patients (n = 69) received adjuvant chemotherapy after surgery. The 3-year distant metastasis-free survival (DMFS) and overall survival (OS) rates were 81.7% and 83.5%. On univariate analyses, poorly differentiated tumors, > 5 cm, involvement of mesorectal fascia (MRF), or presence of extramural involvement (EMVI) were associated with worse DMFS and OS. Five patients showed distant metastasis at their first evaluation after NACRT. Patients with early distant metastasis were more likely to have poorly differentiated tumor (P = 0.025), tumors with involved MRF (P = 0.002), and EMVI (P = 0.012) than those who did not. CONCLUSIONEMVI, the involvement of MRF, and poor histologic grade were associated with early distant metastasis. In order to control distant metastasis and improve treatment outcome, selective use of neoadjuvant treatment according to individualized risk factors is necessary. Future studies are required to determine effective treatment strategies for patients at high risk for distant metastasis.     

Impact of body mass index on treatment outcome of neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Aim

To determine the effect of obesity, measured by body mass index (BMI), on tumor response and surgical outcome in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (nCRT) and radical surgery.

局部晚期直肠癌新辅助放化疗联合免疫治疗的研究进展

对于局部晚期(T3-4/N+M0)直肠癌, 新辅助放化疗联合全直肠系膜切除术的标准治疗模式可以明显减少局部复发、增加肿瘤退缩, 但是远处转移没有得到改善。放疗和免疫治疗相辅相成, 两者联合具有良好的理论基础。近年来, 局部晚期直肠癌新辅助放化疗联合免疫治疗的相关临床试验逐渐展开, 在微卫星不稳定(MSI-H)和微卫星稳定(MSS)患者中均进一步提高肿瘤退缩程度和病理性完全缓解率, 增加器官保留概率, 为"等待观察"策略提供更多可能。新辅助放化疗联合免疫治疗未来仍需要更多的大型临床试验进行验证, 期待能带来更好的生存获益。