Wait-and-see or radical surgery for rectal cancer patients with a clinical complete response after neoadjuvant chemoradiotherapy: a cohort study

A wait-and-see policy might be considered instead of surgery for rectal cancer patients with no residual tumor or involved lymph nodes on imaging or endoscopy after neoadjuvant chemoradiotherapy (clinical complete response, cCR). In this cohort study, we compared the oncologic outcomes of rectal cancer patients with a cCR who were managed according to a wait-and-see policy (observation group) or with surgery (surgery group). In the observation group, follow-up was performed every 3 months for the first year and consisted of MRI, endoscopy with biopsy, computed tomography and transrectal ultrasonography. In the surgery group, patients received radical surgery. Long-term oncologic outcomes were estimated using Kaplan-Meier curves. Thirty patients were enrolled in the observation group (median follow-up, 60 months; range, 18-100 months), and 92 patients were enrolled in the surgery group (median follow-up, 58 months; range, 18-109 months). The 5-year disease free survival and overall survival rates were similar in the two groups: 90.0% vs. 94.3% (P = 0.932) and 100.0% vs. 95.6% (P = 0.912), respectively. We conclude that for rectal cancer patients with a cCR after neoadjuvant chemoradiotherapy, a wait-and-see policy with strict selection criteria, follow-up and salvage treatments achieves outcomes at least as good as radical surgery. Additionally, we declare that the pCR (pathologic complete regression) and non-pCR subgroups of patients with a cCR have similar long-term failure (local recurrence and/or distant metastasis) rate.     

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。     

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.     

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.     

Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal cancer

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新辅助放化疗对mrT3 期低位直肠癌患者不同浸润深度远期疗效的影响*

目的：探讨新辅助放化疗（neoadjuvant chemoradiotherapy ,CRT ）对cT 3 期低位直肠癌及其各亚分期预后的影响,进一步评估是否所有T 3 期低位直肠癌患者均应行CRT 。方法：对2008年1 月至2012年12月间福建医科大学附属协和医院结直肠外科收治的223 例cT 3 期低位直肠癌患者,按北美放射协会（RSNA）影像学分期标准回顾性进行亚分期,即根据高分辨率MRI 测量下肿瘤浸润直肠系膜的深度（depth of mesorectal invasion,DMI）分为mrT3a 期（DMI<5 mm）,mrT3b 期（DMI 为5～10mm）和mrT3c 期（DMI>10mm）,并根据是否行CRT 分为新辅助放化疗组（CRT 组,115 例）和未行新辅助放化疗组（nCRT组,108 例）,比较两组患者及其
各亚分期（mrT3a、mrT3b、mrT3c）之间预后的差异。结果：对于整体mrT3 期,CRT 组和nCRT组的3 年无病生存率（78.2% vs . 71.9% ,P =0.608）和局部复发率（4.4% vs . 8.5% ,P = 0.120）无统计学差异。对于mrT3 各亚分期,CRT 组和nCRT组预后分别为：mrT3a：3 年无病生存率82.4% vs . 81.8%（P = 0.837）、局部复发率5.8% vs . 5.9%（P = 0.658）;mrT3b：3 年无病生存率84.4% vs . 42.4%（P = 0.032）、局部复发率0 vs . 18.2%（P = 0.014）;mrT3b、mrT3c：3 年无病生存率72.8% vs . 42.4%（P = 0.060）、局部复发率2.4% vs . 18.2%（P = 0.021）。 单因素分析提示DMI 和环周切缘（circumferential resection margin ,CRM）是mrT3 期直肠癌患者3 年无病生存时间的影响因素,Cox 风险回归模型多因素分析提示CRM是独立影响因素（OR= 2.249,CI ：1.067～4.742,P = 0.033）。 结论：CRT 能改善mrT3b、mrT3c 期低位直肠癌患者的预后,但可能无法改善mrT3a 且CRM阴性低位直肠癌患者的预后,对这部分患者可直接行手术治疗。     

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m(-2) day(-1) and weekly irinotecan 40 mg m(-2). In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate.     

直肠癌新辅助放化疗前后LGR5基因表达的变化及其与疗效的关系

目的：探讨肿瘤干细胞标记基因LGR5在局部晚期直肠癌新辅助放化疗（放疗同时口服卡培他滨）前后表达的变化,及其对新辅助放化疗效果预测的作用。方法：收集2014年1月-2016年2月在新疆医科大学附属肿瘤医院接受新辅助放化疗并手术治疗的94例局部晚期直肠癌患者临床资料,对其新辅助放化疗前肠镜活检组织及新辅助放化疗后手术切除组织标本采用荧光定量PCR（qPCR）法检测LGR5 mRNA的表达,分析其在新辅助放化疗前后表达水平的变化及其与疗效的关系,采用Kaplan-Meier法进行生存分析,Log-rank法进行单因素预后分析和Cox回归进行多因素预后分析。结果：直肠癌患者接受新辅助放化疗后肿瘤病理退缩反应良好,肿瘤退缩有效率达87.2%,其中病理完全缓解率为18.1%。直肠癌癌组织中LGR5 mRNA的相对表达水平从新辅助放化疗前的14.396±9.924减少到手术后的8.847±6.664,总体表达水平显著下降（P < 0.05）。放化疗后LGR5 mRNA表达上调者27例,表达下调者67例,表达下调组肿瘤病理退缩程度（TRG）和1、2年生存率均明显优于表达上调组（P < 0.05）。单因素生存分析结果显示放化疗前血清CA19-9水平、临床分期、TRG分级和LGR5 mRNA表达差异为直肠癌预后的影响因素（P均 < 0.05）;多因素分析表明放化疗前CA19-9水平和放化疗前后LGR5 mRNA表达差异是直肠癌预后的影响因素（P分别为0.013和0.015）。结论：新辅助放化疗可以诱导LGR5 mRNA表达的改变,检测其表达对于判断直肠癌预后及指导治疗具有参考价值,新辅助放化疗前后LGR5 mRNA表达变化和放化疗前CA19-9水平有可能成为预测局部晚期直肠癌新辅助放化疗效果的参考指标。     

局部晚期直肠癌新辅助治疗后病理完全缓解者的预后分析

目的:总结局部晚期直肠癌新辅助治疗后病理完全缓解（pCR）者的长期预后,探讨术后辅助化疗的必要性。方法:回顾性分析2005年至2014年间,323例在我院进行新辅助治疗及根治性手术的局部晚期直肠癌患者的临床资料,分析pCR者的长期预后,同时比较术后辅助化疗组和术后未化疗组的预后。结果:52例（16.1%）获得pCR,其中1例患者失访;全组患者中位随访时间为53个月,全组5年无病生存率和总生存率分别为82.7%和90.9%。其中22例（43.1%）患者接受术后辅助化疗,29例（56.9%）未接受术后化疗。两组患者的性别、年龄、肿瘤临床分期、肿瘤位置、大小、分化程度、术前CEA水平、新辅助化疗的方案、新辅助治疗结束至手术的间隔周期、手术方式、术后并发症、淋巴结清扫的数目以及随访时间均无统计学差异。两组患者的5年无病生存率以及总生存率亦无统计学差异。结论:局部晚期直肠癌新辅助治疗后病理完全缓解者可获得良好的生存预后;对于pCR者,实施术后辅助化疗不会影响其预后。     

直肠癌新辅助治疗后临床完全缓解的评估

新辅助治疗已成为局部晚期直肠癌的标准治疗模式。新辅助治疗后对肿瘤反应进行评估及再分期对于制定患者后续的治疗策略和预测肿瘤的预后至关重要。有一部分患者在新辅助治疗后能达到临床完全缓解甚至病理完全缓解,而在病理未明确之前如何评估临床缓解一直是目前国内外专家关注的焦点。本文就直肠癌新辅助治疗后的最佳评估时间和评估方法的进展进行综述。     

Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer

This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis-free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch-and-wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19-9 were selected to establish the RPA-based risk stratification, categorizing LARC patients into low-risk (n = 139; CA19-9 < 35 U/mL and CEA < 5 ng/mL) and high-risk (n = 73; CA19-9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5-y DMFS was observed in the low-risk group vs. the high-risk group (92.9% vs. 76.2%, P = .002). Low-risk LARC patients who underwent TME had significantly improved 5-y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high-risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19-9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.     

直肠癌新辅助放化疗后临床完全缓解等待观察策略可行性的Meta分析

目的:比较直肠癌新辅助放化疗后达到临床完全缓解（clinical complete response,cCR）采取等待观察策略和手术切除治疗策略在肿瘤控制及生存期方面的差异,以此阐述等待观察策略的可行性。方法:在国外数据库中检索关于直肠癌新辅助放化疗（nCRT）达到cCR关于等待观察策略和手术切除对比试验的相关文献,按照纳入和排除标准进行文献筛选和质量评估,使用STATA 12.0软件进行Meta分析,对比两组在局部复发、远处转移、肿瘤相关死亡、2年及5年无疾病进展生存期和总体生存期之间的差异。结果:本研究总共纳入9篇文献,Meta分析结果显示:等待观察组相比手术组有着较高的局部复发率（LR）（RR=5.05;95%CI:2.22~11.51;P<0.001),但是两组在远处转移（RR=0.93;95%CI:0.51~1.68;P=0.805）、肿瘤相关死亡（RR=0.83;95%CI:0.37~1.87;P=0.658）、2年无疾病进展生存期（RR=0.97;95%CI:0.91~1.03;P=0.277）、2年总体生存期（RR=1.03;95%CI:0.97~1.10;P=0.346）、5年无疾病进展生存期（RR=0.95,95%CI:0.83~1.08;P=0.406）、5年总体生存期（RR=1.03;95%CI:0.95~1.11;P=0.534）并无统计学差异。结论:对于部分nCRT后达到cCR的患者采用等待观察策略是可行的,但需要制定严格的筛选标准以及规范的随访。     

直肠癌新辅助治疗中盆腔骨髓保护调强放疗与病理反应的相关性

目的:探讨直肠癌新辅助治疗中盆腔骨髓保护调强放疗与病理反应的相关性。方法:回顾性分析2017年01月至2020年12月于我院接受新辅助放化疗及根治性手术的192例Ⅱ、Ⅲ期直肠癌患者的临床病理资料,其中95例为接受盆腔骨髓保护调强放疗的患者(淋巴细胞保护组),余97例患者来源于本单位回顾性数据库(对照组)。比较两组患者淋巴细胞绝对计数最低值、淋巴细胞下降程度及肿瘤病理反应率差异,分析直肠癌新辅助治疗中盆腔骨髓保护调强放疗与病理反应的相关性。结果:淋巴细胞保护组患者放化疗期间最低淋巴细胞计数、放化疗后淋巴细胞计数及病理反应率均高于对照组,差异有统计学意义。淋巴细胞保护组3-4级淋巴细胞减少症发生率为38.9%,低于对照组的56.8%(P=0.034)。多因素Logistic回归分析结果显示3-4级淋巴细胞减少症、淋巴细胞保护、临床分期及等待手术期间化疗是肿瘤病理反应状态的独立影响因素。结论:直肠癌患者新辅助放化疗期间3-4级淋巴细胞减少症与治疗后肿瘤病理反应状态密切相关,通过盆腔骨髓保护调强放疗可有效保护患者的淋巴细胞,减轻3-4级淋巴细胞减少症发生率,提高肿瘤病理反应。     

High FOXP3+ regulatory T-cell density in the sentinel lymph node is associated with downstream non-sentinel lymph-node metastasis in gastric cancer

Background:

We aimed to evaluate the immunologic nature of sentinel lymph nodes (SLNs) in gastric cancer patients and to determine whether it can predict non-SLN metastasis.

Methods:

Sentinel lymph node samples were collected from 64 gastric carcinoma patients who had undergone gastrectomy with SLN biopsy. One representative SLN sample was selected from each patient and was subjected to immunostaining for CD8, CD57, FOXP3, and DC-LAMP. The numbers of marker-positive cells in each sample were counted. The relationships between various immune cell densities and clinicopathologic parameters or metastasis status of SLNs and non-SLNs were sought.

Results:

High FOXP3+ Treg density of the SLN was found to be significantly associated with the presence of metastasis in either SLNs or non-SLNs. DC-LAMP+ cell density of the SLN was the highest at the isolated tumours cell level, and this decreased along with an increase in tumour metastasis in either SLNs or non-SLNs. Univariate and multivariate logistic regression models revealed that high FOXP3+ Treg density of the SLN was an independently significant predictor of non-SLN metastasis.

Conclusions:

This study is the first to indicate an important role of SLNs in metastatic dissemination of gastric cancer. Our findings suggest that Tregs could be a new therapeutic target for regulating the metastasis of gastric cancer.     

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.