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...     

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。     

直肠癌经新辅助治疗后达到临床完全缓解的评估策略及观察和等待策略

术前新辅助放化疗联合全直肠系膜切除术已成为局部晚期直肠癌患者治疗的金标准。临床上部分患者经放化疗治疗后达到病理完全缓解,并与不全缓解患者相比局部复发率显著降低,生存期延长。为了避免手术相关并发症、改善患者生活质量（造瘘和保肛问题）,一些机构尝试对放化疗后临床完全缓解患者采用非手术方案—“观察和等待策略”。然而,临床完全缓解并不总是预示病理完全缓解,需要综合评估策略更准确地预测哪些患者已经达到病理完全缓解来安全行“观察和等待策略”。本文就目前关于非手术方案的数据作一综述并讨论与此方案相关的持续争议。     

局部进展期直肠癌新辅助放化疗后肿瘤退缩的影响因素分析及预测模型构建

背景与目的：局部进展期直肠癌（locally advanced rectal cancer,LARC）的标准治疗策略是新辅助放化疗（neoadjuvant chemoradiotherapy,nCRT）后进行手术治疗,nCRT可以使肿块缩小,实现肿瘤降期,增加R0切除率。但直肠癌个体差异较大,有部分患者对nCRT反应较差,并不能从nCRT中获益。因此,采取有效的筛选措施,以识别nCRT效果不佳的患者很有必要。本研究旨在探讨临床基线指标对LARC nCRT后肿瘤退缩的预测价值并构建肿瘤退缩预测模型。方法：收集2016年1月—2020年12月在空军军医大学第一附属医院接受nCRT治疗且行全直肠系膜切除术的LARC患者,收集入组患者nCRT前的临床基线指标,包括实验室检查、肿瘤标志物和磁共振成像（magnetic resonance imaging,MRI）资料。根据nCRT前后的MRI报告的肿瘤大小,通过实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors,RECIST）来评价LARC患者nCRT后肿瘤退缩程度。使用受试者工作特征（r...     

局部进展期直肠癌新辅助治疗研究进展

直肠癌是常见的消化道恶性肿瘤,手术难度大,术后并发症较为常见,局部复发率较高,尤其以局部进展期直肠癌(LARC)的治疗效果差。随着多学科综合治疗理念在恶性肿瘤诊疗过程中受到重视,局部进展期直肠癌患者的预后也在术前新辅助治疗的应用下得以改善。因新辅助放化疗能有效降低术后局部复发率,新辅助放化疗联合全直肠系膜切除术(TME)已成为局部进展期直肠癌国际公认的治疗模式,临床医生也逐渐重视该疾病的术前治疗。为探求更佳的直肠癌患者的综合治疗方案,通过阅读国内外相关文献,就直肠癌新辅助治疗的现状与研究进展进行综述。     

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。     

直肠癌新辅助放化疗后cCR患者不同治疗方法随访观察

目的 通过比较新辅助放化疗后cCR的直肠癌患者采用非手术治疗和TME治疗的效果,旨在探讨非手术治疗策略的可行性。方法 选取2006—2016年中山大学肿瘤防治中心接受术前放化疗并获得cCR的135例Ⅱ、Ⅲ期直肠癌患者,根据治疗方法的不同将其分为非手术组(43例NOM组)和标准手术组(92例SOM组)。比较2组患者的局部复发率、挽救性治疗后的累计LC率、DFS、OS以及保肛率等。Kaplan-Meier法计算LC、OS、DFS并Logrank法检验,χ²检验保肛率。结果 中位随访39个月(10~127个月)。135例患者的局部复发率及远处转移率分别为3.7%和11.1%,术后3年DFS和OS分别为90.5%和97.0%。NOM组与SOM组术后3、5年DFS率分别为87%与93%、73%与87%(P=0.089),OS率分别为98%与99%、98%与97%(P=0.578)。NOM组局部复发5例(12%),80%患者得到挽救性治疗,累计LC率为98%;SOM组无局部复发病例;两组差异有统计学意义(P=0.010)。NOM组保肛率为93%,显著高于SOM组的70%(P=0.030)。结论 新辅助放化疗后获得cCR的直肠癌患者采取非手术治疗策略是可行的,部分局部复发患者仍可通过及时的挽救性治疗痊愈,从而有效避免了TME及其并发症,提高了患者的生活质量。     

低位直肠癌术前同步放化疗的远期疗效及安全性研究

目的评估术前口服卡培他滨（希罗达）与放疗联合治疗局部进展期低位直肠癌的远期疗效及安全性。方法对局部进展期（T3／T4）低位直肠腺癌（距肛缘≤9Ccm）患者51例,术前给予口服卡培他滨（希罗达）并联合放疗。放疗结束后休息3—4周,按TME原则进行手术。结果3例患者临床完全消退（cCR）,占5．88％,未行手术;其余48例患者均行根治性切除术（R0）,实际保肛率90．20％（46／51）,10例术后病理检查未见肿瘤细胞,为病理消退（pCR）,总消退率为25．49％（13／51）。肿瘤降期41例,占80．39％。5年无病生存率为70．59％,总生存率为80．39％。放化疗过程中出现3、4级不良反应5例,无疾病进展、手术死亡者。结论术前口服卡培他滨联合放疗治疗局部进展期低位直肠癌是有效安全的。     

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。     

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。     

Feasibility study of a Response Surveillance Program in locally advanced mid and low rectal cancer to increase organ preservation

BackgroundAssessment of tumor response in rectal cancer after neoadjuvant treatment by MRI (Tumour Regression Grade, TRG 1–5) is well standardized. The overall timing and method of defining complete response (cCR) remain controversial. The aim of this work was to evaluate the feasibility of a defined Response Surveillance Program (RSP) to increase organ preservation for locally advanced rectal cancer after neoadjuvant treatment.MethodsA standardized program of clinical (CR), radiological (RR) and metabolic (MR) assessment of tumor response is defined over a 6 month period from completion of NACRT with formal assessment performed every 2 months (M). Patients with TRG1-3 at M2 and TRG1-2 at M4 continue in the program up to M6 assessment. Patients managed with this protocol from 2016 to 2020 were analyzed. The primary endpoint was rectal preservation rate. Secondary endpoints included disease-free survival and overall survival at 3 years.Result314 potentially suitable patients were enrolled in the RSP and 50 patients completed the six month program and were successfully enrolled into watch and wait. Fourteen (28%) were T2 tumor stage, 27 (54%) T3 and nine (18%) were T4. During watch and wait, patients with locoregional recurrence (n = 11) were treated with local excision (n = 3), endocavitary radiotherapy (n = 1), TME (n = 5) and APR (n = 2). With a median follow-up of 32 months, the rectal preservation rate was 88%, with a 3-year disease-free survival of 67% and an overall survival of 98%.ConclusionThis study validates the feasibility of the practical implementation of a Response Surveillance Program to increase organ preservation rates without compromising oncological outcomes in rectal cancer.     

Individualizing surgical treatment based on tumour response following neoadjuvant therapy in T4 primary rectal cancer

BackgroundRectal cancer involving at least one adjacent organ (mrT4b) requires multi-visceral resection to achieve clear resection margin (R0). Performing pelvic compartment preservation according to the tumour response has not been considered. This study assesses the impact of changing the surgical strategy according to tumour response in rectal cancer mrT4b.MethodsPatients with non-metastatic T4b rectal cancer at two tertiary referral centres between 2008 and 2013 were grouped as “Responders” ypT0-3abNx versus “Non-responders” ypT3cd-4Nx and divided into three surgical procedures: total mesorectal excision (TME), extended-TME (eTME) and beyond-TME (b-TME). End-points were circumferential resection margin, postoperative morbidity, definitive stoma formation, 3-years local recurrence (3y-LR) and 3-years disease-free survival (3y-DFS) according to both tumours' response and surgical procedures.ResultsAmong 883 patients with rectal cancer, 101 were included. Responders had a higher rate of induction chemotherapy (59.7% vs. 38.2%; p = 0.04). Morbidity and definitive stoma formation were significantly higher in Non-responders. R0 was not impacted by either the tumour response or the surgical procedures. The 3y-LR was lower in Responders (14%) compared to Non Responders (32%) (HR 1.6; 95% CI: 1.02–2.59; p = 0.041), and was two-fold higher in e-TME compared to b-TME in Non-responders, whereas no difference was found in Responders. The 3y-DFS was higher in Responders irrespective to the surgery (71% vs. 47%; p = 0.07).ConclusionIn Responders, TME or e-TME are technically and oncollogically feasible and should be considered in preferrence to b-TME. In Non-responders, allowing for high rates of morbidity and local recurrence in patients with e-TME, b-TME procedures should be preferred.     

Initial magnetic resonance imaging tumour regression grade (mrTRG) as response evaluation after neoadjuvant treatment predicts sustained complete response in patients with rectal cancer

PurposeReliable predictors of a sustained clinical complete tumour response (cCR) after neoadjuvant therapy in rectal cancer (RC) are lacking. The aim of this study was to determine if the tumour regression grade (TRG) assessed by magnetic resonance imaging (MRI), at the first restaging after neoadjuvant therapy can predict organ preservation, and to estimate the time interval after which surgery should be recommended in patients who remain in near cCR.Materials and methodsEighty-three consecutive patients were assessed by MRI as having a cCR (mrTRG 1) or near cCR (mrTRG 2) after neoadjuvant therapy. Cox proportional hazards regression models and Kaplan-Meier survival analyses were used to determine associations between resection-free survival (RFS) and mrTRG at the first restaging, and in relation to mrTRG with a landmark period. mrTRG and pathological findings were compared in operated patients.ResultsmrTRG 2 at the first restaging significantly predicted poorer RFS during follow up. The best prediction of RFS was mrTRG at landmark 16 weeks after termination of radiotherapy; 42 out of 49 patients (86%) evaluated as mrTRG 1 had cCR at one year of follow up. In contrast, 12 out of 15 patients (80%) evaluated as mrTRG 2 had clinical signs of tumour and were recommended surgery.ConclusionsThe first mrTRG, and to an even greater extent mrTRG at landmark 16 weeks predicts RFS. Patients who remain mrTRG 2 at 5–6 months after radiotherapy with signs of tumour should be recommended surgery. These findings may help in patient counselling and surgical decision-making.     

Global variation in the long-term outcomes of ypT0 rectal cancers

BackgroundColorectal cancer mortality presents world-wide variation. In rectal cancers presenting a complete/nearly-complete tumor response (ypT0/ypTis) following neoadjuvant treatment, the features correlated to nodal metastases and relapses still need to be defined.MethodsAn international cohort study enrolling ypT0/ypTis rectal cancers surgically treated from 2012 to 2017 was conducted. A propensity matching was used to balance nodal-positive and nodal-negative patients and statistical analyses were performed to investigate survivals, using a bootstrap model for internal validation. The features correlated with nodal metastasis were studied. Countries with participating centers were ranked using the World Bank (WBI), Human Development (HDI) and Global Gender Gap (GGG) indexes to compare survivals.Results680 ypT0/ypTis from 52 European, Australian, Indian and American Institutions were analyzed. Mean follow-up was of 30.4 months. 96.5% were treated with total mesorectal excision, 7.2% were nodal-positive and 8.8% relapsed. Distal cancers (HR 0.71 95%CI: 0.56-0.91) and nodal metastasis and nodal metastasis (HR 3.85 95%CI:1.12–13.19) correlated with worse DFS, whereas a younger age was of borderline significance (HR 0.95 95%CI:0.91–0.99). The bootstrap analysis validated the model on 5000 repetitions. A short-course radiotherapy (OR 0.18 95%CI:0.09–0.37) correlated with the occurrence of nodal metastasis. Those countries classified in the low/medium-WBI, medium-HDI and lower-GGG ranks documented worse DFS curves (respectively p < 0.0001, p < 0.0001 and p 0.0002). However, the clinical stages were similar and patients from medium-HDI countries received more adjuvant chemotherapy than the others (p < 0.0001).ConclusionSub-groups at risk for relapses and nodal metastasis were identified. A global variation exists also when benchmarking a rectal cancer complete regression.     

Advances in organ preserving strategies in rectal cancer patients

Treatment of rectal cancer patients has been subjected to change over the past thirty years. Total mesorectal excision is considered the cornerstone of rectal cancer treatment, but is also associated with significant morbidity resulting in an impaired quality of life. The addition of neoadjuvant chemoradiotherapy to surgery has shown to improve survival and local control and may lead to a partial or even complete response (CR). This raises questions regarding the necessity for subsequent radical surgery. After careful patient selection local excision and wait-and-see approaches are explored, aiming to improve quality of life without compromising oncological outcome. A multimodality diagnostic approach for optimal staging is crucial in determining the appropriate neoadjuvant treatment regimen. Adequate endoscopic restaging of rectal tumours after multimodality treatment will aid in selecting patients who are eligible for an organ preserving approach. The role and accuracy of imaging in the detection of the primary tumour, residual rectal cancer or local recurrence seems vital. Alternative neoadjuvant regimens are currently explored to increase the rate of clinical CRs, which may support organ preserving approaches. This review aims to generate insight into the advances in diagnostics and treatment modalities in all stages of rectal cancer and will highlight future studies that may support further implementation of organ preservation treatment in rectal cancer.     

Consolidation chemotherapy with capecitabine after neoadjuvant chemoradiotherapy in high-risk patients with locally advanced rectal cancer: Propensity score study

BACKGROUNDThe effects of consolidation chemotherapy (CC) in neoadjuvant therapy in locally advanced rectal cancer (LARC) have been explored. However, the optimal neoadjuvant chemoradiotherapy (NCRT) and surgery interval, regimen, and cycles of chemotherapy remains unclear.AIMTo evaluate the effects of one to two cycles of CC with capecitabine on high-risk patients with LARC without extending NCRT and surgery interval.METHODSWe retrospectively evaluated high-risk patients with LARC, who were defined as having at least one of the following factors by magnetic resonance imaging: depth of invasion beyond the muscularis propria of more than 5 mm (cT3c-cT3d), T4, meso-rectal fascia or extramural vascular invasion positive, and treatment date between January 2015 and July 2019 in our center. Patients were divided into the CC and non-CC group according to whether they received CC (capecitabine 1000 mg/m² twice daily from days 1 to 14 every 21 d) after NCRT. Propensity score matching (PSM) and inverse probability of treatment weight (IPTW) were used to balance the differences between the two groups. The main outcome was the complete response (CR) rate.RESULTSA total of 265 patients were enrolled: 136 patients in the CC group and 129 patients in the non-CC group. The median interval was 70 d (range, 37-168). The CR rate was 24.3% and 16.3% (P = 0.107) in the CC and non-CC groups’ original samples, respectively. After PSM and IPTW, the CR rate in the CC group was higher than that in non-CC group (27.6% vs 16.2%, P = 0.045; 25.9% vs 16.3%, P = 0.045). The median follow-up was 39.8 mo (range, 2.9-74.8), and there were no differences in 3-year non-regrowth disease-free survival nor overall survival in the original samples (73.2% vs 71.9%, P = 0.913; 92.3% vs 86.7%, P = 0.294), PSM (73.2% vs 73.5%, P = 0.865; 92.5% vs 89.3%, P = 0.612), and IPTW (73.8% vs 72.1%, P = 0.913; 92.4% vs 87.4%, P = 0.294). There was also no difference in grade 2 or higher acute toxicity during neoadjuvant therapy in the two groups (49.3% vs 53.5%, P = 0.492).CONCLUSIONOne to two cycles of CC with capecitabine after NCRT was safe and increased the CR rate in high-risk LARC but failed to improve the long-term outcomes.     

Role of radiotherapy in the treatment of rectal cancer in older patients

Striking a balance between cancer treatment and patient-centred care is becoming ever more important in older patients with rectal cancer as the population is ageing. The treatment decision made by the modern multidisciplinary colorectal team will recommend pre-operative chemo-radiotherapy followed by surgery for advance rectal cancer and surgery alone for early rectal cancer, as the “standard of care” is surgery. However, an alternative non-surgical treatment option should be consider for older patients with rectal cancer as the surgical harm can far outweigh the potential benefits. There is published evidence that mortality is higher with increasing age. An alternative treatment option to surgery when patients are not suitable or refusing surgery is to offer them external beam radiotherapy (EBRT) or chemo radiotherapy (EBCRT). A proportion of these patients can achieve a clinical complete response (cCR) which enable adoption of ‘watch and wait’ strategy to avoid surgery. However, a third of patients who achieved initial cCR can develop local regrowth within the first two years. This require salvage surgery which reduces their chance of organ preservation. Contact X-ray brachytherapy (CXB) or High Dose Rate Endo Brachy Therapy (HDREBT) boost following external beam radiotherapy can improve the initial cCR rate and reduce the risk of local regrowth. Those patients with persistent residual cancer or regrowth after brachytherapy boost following EBCRT or EBRT can have salvage surgery later without compromising their chance of cure. Therefore, patients should be fully aware of their treatment options and have ‘a choice’ when deciding and consenting their treatment.     

STAR-TREC: An International Three-arm Multicentre,Partially Randomised Controlled Trial Incorporating an External Pilot

AimOrgan saving treatment for early-stage rectal cancer can reduce patient reported side effects compared to standard total mesorectal excision (TME) and preserve quality of life (QOL). An optimal strategy for achieving organ preservation and longer-term oncological outcomes are unknown, thus there is a need for high quality trials.MethodCan we Save the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR-TREC) is an international 3-arm multi-centre, partially randomised controlled trial incorporating an external pilot. In phase III, patients with cT1-3b N0 tumours, ≤40mm in diameter, who prefer organ preservation are randomised 1:1 between mesorectal long course chemoradiation versus mesorectal short course radiotherapy, with selective transanal microsurgery. Patients preferring radical surgery receive TME. STAR-TREC aims to recruit 380 patients to organ preservation and 120 to TME surgery. The primary outcome is the rate of organ preservation at 30 months. Secondary clinician reported outcomes include acute treatment-related toxicity, rate of non-operative management, non-regrowth pelvic tumour control at 36 months, non-regrowth disease free survival at 36 months, and overall survival at 60 months and patient reported toxicity, health related QOL at baseline, 12 and 24 months. Exploratory biomarker research uses circulating tumour DNA to predict response and relapse.DiscussionSTAR-TREC will prospectively evaluate contrasting therapeutic strategies and implement new measures including a smaller mesorectal target volume, 2-step response assessment and non-operative management for complete response. The trial will yield important information to guide routine management of patients with early-stage rectal cancer.     

291例局部进展期直肠癌术前新辅助放化疗的临床意义分析

目的 评价局部进展期直肠癌(LARC)术前新辅助放化疗的疗效及安全性。方法 2003—2012年间291例LARC接受了术前新辅助放化疗+手术±术后辅助化疗。放疗为2DRT、3DRT,45~50 Gy分23~25次。化疗方案包括FOLFOX6、XELOX及单药希罗达等,术前化疗2~4周期。放疗结束后3~8周手术,遵循全直肠系膜切除术原则。134例患者术后接受了辅助化疗。Kaplan-Meier法计算OS、DFS、RFS和DMFS等,Logrank法检验和单因素预后分析,Cox模型多因素预后分析。结果 全组均完成术前新辅助放化疗及手术。R0切除率为98.9%,保肛率为53.6%。T降期73.1%,N降期83.6%,临床分期降期79.4%。pCR率为26.8%,3级血液系统反应为7.9%,3级腹泻为7.2%,3级放射性皮炎为2.7%。术后会阴部疼痛占12.3%,伤口延迟愈合占8.2%。随访率94.5%,5年样本量为95例。5年OS、DFS、RFS和DMFS分别为76.6%、72.1%、88.8%和79.7%,5年LR率为7.5%,远处转移率为15.8%。术后病理分期是预后影响因素。结论 术前新辅助放化疗提高了LARC的R0切除率及保肛率,并使肿瘤显著降期,不良反应较轻且未增加手术并发症,LR率低且远期生存率得到改善。术前新辅助放化疗作为LARC标准治疗策略宜推广应用。