局部进展期直肠癌新辅助放化疗的研究进展

术前放化疗联合全系膜切除手术为局部晚期直肠癌患者治疗的标准模式,术前放化疗比术后放化疗提高了肿瘤降期率、保肛率及局部控制率,术前放化疗后达到病理完全缓解患者拥有更好的预后。本文就近年来术前放化疗的研究进展作一综述。     

局部进展期直肠癌新辅助放化疗的研究进展

术前放化疗联合全系膜切除手术为局部晚期直肠癌患者治疗的标准模式,术前放化疗比术后放化疗提高了肿瘤降期率、保肛率及局部控制率,术前放化疗后达到病理完全缓解患者拥有更好的预后。本文就近年来术前放化疗的研究进展作一综述。     

局部晚期直肠癌新辅助放化疗研究进展

直肠癌是最常见的恶性肿瘤之一,近年来发病率及死亡率日趋升高。患者确诊时大多为中晚期,新辅助放化疗可有效提高局部晚期直肠癌患者的局部控制率、保肛率及病理缓解率,进而改善患者预后。局部晚期直肠癌异质性明显,多项研究对新辅助治疗的具体方案进行探索,如何优化新辅助治疗模式是进一步研究的热点。文章对近年来局部晚期直肠癌新辅助放化疗的研究进展做一综述,为局部晚期直肠癌的精准化医疗提供了参考。     

Stepwise neoadjuvant chemoradiotherapy in the management of mid-low locally advanced rectal cancer

BackgroundThis study aimed to compare the treatment response, complications and prognosis in mid-low locally advanced rectal cancer (LARC) patients who underwent stepwise neoadjuvant chemoradiotherapy (SCRT) or traditional neoadjuvant chemoradiotherapy (CRT).MethodsThe medical records of patients with mid-low rectal cancer who underwent SCRT or CRT were retrospectively analyzed. Differences in the treatment response, pathologic complete response (pCR), R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation, defunctioning stoma, treatment-emergent adverse events (TEAEs), overall survival (OS) and disease-free survival (DFS) between patients who underwent SCRT and CRT were compared.ResultsA total of 430 medical records were investigated, including 194 patients in the SCRT group and 236 patients in the CRT group. There was no significant difference in the rates of treatment response, pCR, R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation or TEAEs between the two groups. However, the rate of defunctioning stoma in the SCRT group was significantly lower than that in the CRT group (20.1% vs. 44.1%, respectively, P < 0.01). Moreover, the median OS time of the SCRT and CRT groups was 44.0 and 50.5 months, respectively (P = 0.17). The median DFS time of the SCRT and CRT groups was 41.0 and 46.8 months, respectively (P = 0.32).ConclusionCompared with the CRT group, the SCRT group had a similar treatment response, local control and long-term prognosis, and more importantly, a portion of the patients in the SCRT group were exempted from excessive radiation.     

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.     

局部进展期直肠癌新辅助治疗后器官保留策略进展

新辅助放化疗联合全直肠系膜切除术为分期T 3-T 4期或N+的局部进展期直肠癌(LARC)的标准治疗,但往往会带来一系列术后并发症,尤其是接受腹会阴联合直肠癌根治术(Mile′s术)不能保留肛门者,严重影响生活质量。对于新辅助治疗后肿瘤(近)临床完全缓解者,器官保留策略在与根治性手术达到相似治疗疗效...     

局部进展期低位直肠癌新辅助放化疗初步临床观察

目的 探讨局部进展期低位直肠癌新辅助放化疗疗效。方法 回顾分析2014-2018年间入组的46例局部进展期低位直肠癌患者,肿瘤下缘距肛缘6cm内。术前放疗采用SIB-IMRT技术,直肠肿瘤及阳性淋巴结照射58.75Gy分25次(2.35 Gy/次),盆腔淋巴引流区照射50Gy分25次(2.0 Gy/次),同步口服卡培他滨进行化疗。放化疗结束后间隔6~12周行直肠癌根治术。Kaplan-Meier法计算总生存(OS)、无瘤生存(DFS)、无进展生存(PFS),无局部复发生存(LRFS)、无转移生存(MFS)。单因素分析用log-rank法检验,多因素分析用Cox回归模型。结果 中位随访时间为47个月,局部复发3例,远处转移6例,ypCR率为26%(12/46),保肛手术率为74%(34/46),R0切除率为100%(44/44),TN总降期率为87%(40/46),术后并发症发生率为13%(6/46)。3年OS、DFS、PFS分别为93%、91%、87%。单因素分析显示ypN分期是影响OS、DFS、PFS、LRFS、MFS的重要因素(均P<0.05),多因素分析显示ypN分期与DFS、PFS、LRFS、MFS均显著相关(均P<0.05)。 结论 局部进展期低位直肠癌患者行术前SIB-IMRT 58.75 Gy分25次联合卡培他滨化疗方案安全可行,提高了ypCR率及生活质量,不良反应可耐受,长期生存是否获益有待进一步深入研究。     

Nucleic acid-based markers of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer

The progress that has been made in the treatment of rectal cancer has mostly resulted from multimodality strategy approach that combines surgery, chemotherapy and radiotherapy. In locally advanced rectal cancer (LARC), surgery remains the primary treatment, while neoadjuvant chemoradiotherapy (nCRT) is used to downsize or downstage the tumor before surgical resection. Highly variable response to nCRT observed in LARC patients raises the need for biomarkers to enable prediction and evaluation of treatment response in a more efficient and timely manner than currently available tools. The search for predictive biomarkers continues beyond blood proteins, which have failed in subsequent validation studies. This review presents nucleic acids-based markers and their predictive potential in LARC patients. Most of the candidate biomarkers come from relatively small single-institution studies. The only candidate biomarker that emerged as relevant in more than a single study was elevated levels of Fusobacterium nucleatum nucleic acids in tumor tissue. Considering that this marker is easily accessible through non-invasive analysis of faecal samples, its predictive potential is worth further validation. The other candidate nucleic acid-based biomarkers require more consistent studies on larger cohorts before they can be considered for use in clinical setting.     

Preliminary clinical observation of neoadjuvant chemoradiotherapy for low and locally advanced rectal cancer

Objective To evaluate the efficacy of preoperative neoadjuvant chemoradiotherapy for low and locally advanced rectal cancer. Methods Clinical data of 46 patients with low rectal tumors located within 6 cm from the edge of anal admitted to our hospital between February 2014 and December 2018 were retrospectively analyzed. SIB-IMRT technique was adopted for preoperative radiotherapy. Rectal tumors and positive lymph nodes were irradiated with a dose of 58.75 Gy in 25 fractions (2.35 Gy/fraction), and pelvic lymphatic drainage area was given with 50 Gy in 25 fractions (2.0 Gy/fraction). Oral administration of capecitabine was delivered for concurrent chemotherapy. Radical surgery for rectal cancer was performed at 6 to 12 weeks after the end of chemoradiotherapy. The overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), local recurrence-free survival (LRFS) and metastasis-free survival (MFS) were calculated by using Kaplan-Meier method. Univariate analysis was conducted by log-rank test, and multivariate analysis was performed by Cox’s regression model. Results After a median follow-up of 47 months, local recurrence occurred in 3 patients and distant metastasis in 6 patients. The ypCR rate was 26%(12/46), the sphincter-preservation rate was 74%(34/46), the R0 resection rate was 100%(44/44), the overall tumor response TN down staging rate was 87%(40/46), and the postoperative complication rate was 13%(6/46). The 3-year OS, DFS, and PFS were 93%,91% and 87%, respectively. In univariate analysis, ypN staging was an important factor affecting OS, DFS, PFS, LRFS and MFS (all P<0.05). In multivariate analysis, ypN staging was significantly correlated with DFS, PFS, LRFS and MFS (all P<0.05). Conclusions Preoperative SIB-IMRT 58.75 Gy in 25 fractions combined with capecitabine chemotherapy is a safe and efficacious treatment for patients with low and locally advanced rectal cancer, which improves the ypCR rate and quality of life, and yields tolerable adverse reactions. Nevertheless, the long-term survival benefits remain to be validated.     

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。     

局部晚期直肠癌新辅助治疗pCR相关因素研究

目的 评价局部晚期直肠癌新辅助治疗后pCR的相关影响因素。方法 回顾分析2011—2013年间收治的265例AJCC分期Ⅱ、Ⅲ期直肠癌患者资料。所有患者均接受新辅助治疗±等待手术间期化疗, 而后手术。运用单因素和二元Logistic回归多因素分析影响pCR的预测因素, 并根据预测危险因素进行归类后分为无风险组(无因素)、低风险组(1个因素)、高风险组(2个因素)。建立临床风险评估模型。因素分析运用二元Logistic回归模型。结果 达pCR者50例(18.9%)。单因素分析中新辅助治疗前CEA、放化疗前T分期、同期放化疗结束至手术间隔时间和放化疗前肿瘤最大厚度对pCR有影响(P=0.017、0.001、0.000、0.040), 多因素分析显示新辅助治疗前CEA水平和同期放化疗结束至手术间隔时间是pCR影响因素(P=0.021、0.001), 进一步分层分析表明只有非吸烟组中新辅助治疗前低水平CEA对pCR有影响(P=0.044)。临床风险评估模型诊断pCR的敏感性为80.5%, 特异性为46.0%, AUC为0.690, 阳性预测值为35.49%, 阴性预测值为86.5%, 准确性为73.9%。结论 新辅助治疗能使部分局部晚期直肠癌患者达pCR。新辅助治疗前低水平CEA和更长的同期放化疗结束至手术间隔时间是局部晚期直肠癌新辅助治疗pCR的预测因素, 而新辅助治疗前低水平CEA对pCR预测只在非吸烟人群中有效。根据新辅助治疗前CEA>5 ng/ml和同期放化疗结束至手术间隔时间≤8周的危险因素建立的临床风险评估模型可用于预测局部晚期直肠癌新辅助治疗pCR率。     

Lymph node regression grading of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy

Neoadjuvant chemoradiotherapy (nCRT) and total rectal mesenteric excision are the main standards of treatment for locally advanced rectal cancer (LARC). Lymph node regression grade (LRG) is an indicator of prognosis and response to preoperative nCRT based on postsurgical metastatic lymph node pathology. Common histopathological findings in metastatic lymph nodes after nCRT include necrosis, hemorrhage, nodular fibrosis, foamy histiocytes, cystic cell reactions, areas of hyalinosis, residual cancer cells, and pools of mucin. A number of LRG systems designed to classify the amount of lymph node regression after nCRT is mainly concerned with the relationship between residual cancer cells and regressive fibrosis and with estimating the number of lymph nodes existing with residual cancer cells. LRG offers significant prognostic information, and in most cases, LRG after nCRT correlates with patient outcomes. In this review, we describe the systematic classification of LRG after nCRT, patient prognosis, the correlation with tumor regression grade, and the typical histopathological findings of lymph nodes. This work may serve as a reference to help predict the clinical complete response and determine lymph node regression in patients based on preservation strategies, allowing for the formulation of more accurate treatment strategies for LARC patients, which has important clinical significance and scientific value.     

直肠癌新辅助放化疗后的非手术治疗

新辅助放化疗目前已成为临床Ⅱ、Ⅲ期直肠癌的标准辅助治疗方式。接受新辅助治疗的患者部分可达到病理完全缓解,即切除的样本中不存在癌细胞。达到临床完全缓解的患者,取消手术治疗后仍获得较好的生存率。临床是否可以通过筛选取消部分患者的手术治疗,以避免术中及术后可能存在的风险及不良反应成为值得探讨的问题。     

直肠癌新辅助放化疗临床效果的评估

直肠癌是常见的恶性肿瘤,直肠癌发病率近年有上升趋势。全直肠系膜切除术（total mesorectal excision ,TME ）是直肠癌的最主要治疗手段,但局部进展期直肠癌患者术后局部复发率高、保肛率低,新辅助放化疗成为局部晚期直肠癌的优选治疗手段。直肠癌新辅助治疗后的临床效果是临床医生关注的焦点。直肠癌新辅助治疗效果的预测及评估关系到后续治疗方案的选择,影响患者的生存期及生活质量。     

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.     

直肠癌新辅助放化疗抵抗性的基因组学预测研究

目的 基于加权基因共表达网络(WGCNA)从分子水平寻找影响直肠癌放化疗抵抗的枢纽基因。方法 于基因表达数据库获得接受放化疗患者的全基因组表达数据GSE119409,分别构建放化疗病理完全缓解组与未获得病理完全缓解组的加权基因共表达网络。利用NetRep保守性评估方法综合分析网络模块各个节点基因连接度、基因显著性与网络位置属性,确定与直肠癌放化疗抵抗性密切相关的枢纽基因。结果 通过WGCNA方法共获得5个(black、blue、green、yellow、purple)与放化疗抵抗性密切相关的网络模块,筛选出5个(SLC22A14、SIDT2、CABP4、EPHB6、RAB11B)与直肠癌放化疗抵抗性相关的枢纽基因。结论 通过加权基因共表达网络分析方法共筛选出与直肠癌放化疗抵抗性相关的5个基因共表达网络模块及相应的5个枢纽基因,为寻找术前放化疗抵抗性评估分子标志物及潜在的治疗靶点提供了线索。     

局部进展期直肠癌新辅助放化疗后缓解率的准确性评估

新辅助放化疗是局部进展期直肠癌术前的首选辅助治疗,其使肿瘤降期、降级的作用已得到广泛认可.部分局部进展期直肠癌患者经新辅助放化疗后可达到临床完全缓解(cCR),经术后病理证实为病理完全缓解(pCR).而准确评估缓解率对制定局部进展期直肠癌的后续治疗策略有重要指导作用,本文主要对局部进展期直肠癌缓解率的准确性评估予以综述.     

新辅助放化疗热疗联合腹腔镜手术治疗进展期直肠癌的临床疗效

目的探讨新辅助放化疗、热疗联合腹腔镜手术治疗进展期直肠癌的临床疗效。方法收集2009年1月至2010年1月收治的86例进展期直肠癌患者,随机分为观察组和对照组,每组43例。观察组患者给予新辅助放化疗、热疗联合腹腔镜手术治疗;对照组患者给予新辅助放化疗联合腹腔镜手术治疗。观察两组患者肿瘤缓解情况、手术相关指标和远期预后情况。结果观察组患者治疗总有效率为53．5％,TNMⅠ期3例、Ⅱ期11例、Ⅲ期29例,均优于对照组;观察组患者的手术时间、手术中出血量、手术后引流量、排气时间、下床时间以及发生吻合口瘘、局部复发、远处转移的情况均明显少于对照组;3年存活率（81．4％）明显高于对照组（55．8％）。结论新辅助放化疗、热疗联合腹腔镜手术治疗能够在手术前降低肿瘤分期、减小手术创伤、促进手术后恢复、改善预后,具有积极的临床价值。     

Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy

Tumor regression grading (TRG) reportedly has prognostic value in rectal cancer patients after pre-operative chemoradiotherapy (CRT). The aim of this retrospective study was to differentiate gene expression profiles based on TRG in residual cancer cells after CRT. We evaluated pathological response using the criteria of four TRG systems: the Japanese Society for the Cancer of Colon and Rectum (JSCCR), Mandard, Dworak and R?del. Total RNA was obtained using microdissection from 52 locally advanced rectal cancer specimens from patients who underwent pre-operative CRT to examine the expression levels of 20 genes [PCNA, MKI67, CDKN1A (p21Cip1), CDK2, CHEK1, PDRG1, LGR5, PROM1 (CD133), CD44, SOX2, POU5F1 (OCT4), LKB1, VEGF, EGFR, HGF, MET, HIF1, GLUT1, BAX and BCL2] using real-time quantitative RT-PCR. Gene expression was compared across the four TRG systems. LGR5 gene expression levels in CRT non-responders were significantly higher than in responders in all four grading systems. Patients with elevated PDRG1 and GLUT1 gene expression had poor pathological response in three TRG systems (JSCCR, Dworak and R?del). MKI67 gene expression in non-responders was significantly higher than in responders in two grading systems (JSCCR and R?del). While, BAX gene expression in responders was significantly higher than in non-responders in the Mandard TRG system. The results of this study suggest that TRG may reflect characteristics, such as proliferative activity, stemness potency and resistance to hypoxia, of residual cancer cells following pre-operative CRT.