Adjuvant and neoadjuvant radiotherapy and concurrent radiochemotherapy for rectal cancer

Radical surgery with negative margins remains the most important prognostic factor in the treatment of rectal cancer. Combined modality treatment is the recommended standard adjuvant therapy for patients with locally advanced rectal cancer in the USA and in Germany. During the last decade substantial progress has been made in treatment modalities: surgical management currently includes a broad spectrum of operative procedures ranging from radical operations to innovative sphincter-preserving techniques. Specialized groups have reported excellent local control rates with total mesorectal excision (TME) alone. New and improved radiation techniques (conformai radiotherapy, intraoperative radiotherapy) and innovative schedules (protracted intravenous infusion, chronomodulated infusion) and combinations (oxaliplatin, irinotecan) of chemotherapy may have the potential to further increase the therapeutic benefit of adjuvant treatment. Moreover, the basic issue of timing of radio-(chemo-) therapy preoperative versus postoperative within a multimodality regimen is currently being addressed in prospective trials. Evidently, the current monolithic approaches, established by studies conducted more than a decade ago, to apply either the same schedule of postoperative radiochemotherapy to all patients with stage II/III rectal cancer or to give preoperative intensive short-course radiation according to the Swedish concept for all patients with resectable rectal cancer irrespective of tumor stage and treatment goal (e.g. sphincter preservation), need to be questioned. This review will discuss different irradiation settings in more recent and ongoing studies of perioperative radiotherapy for rectal cancer and will focus on the issue which patient should receive radiotherapy at all, and if so, how and when?     

Comparison of pathological complete response rates after neoadjuvant short-course radiotherapy or chemoradiation followed by delayed surgery in locally advanced rectal cancer

Introduction

Patients with locally advanced rectal cancer (LARC) who are unfit for chemoradiation (CRT), are often offered short-course radiotherapy followed by delayed surgery (SCRT-delay). This entails a lower radiation dose, no chemotherapy and a shorter treatment period. This may lower their chances for complete tumor response and, as such, organ-sparing approaches. The purpose of this study was to compare the pathological complete response (pCR) rates between neoadjuvant CRT and SCRT-delay in patients with LARC in a nationwide database from the Netherlands.

直肠癌新辅助放疗研究进展

在过去的近40年里,直肠癌的治疗方案逐渐标准化。大多数早期直肠癌患者仅通过手术即可得到充分的治疗。然而,相当比例的直肠癌患者处于局部进展期,此类患者需要行新辅助治疗。直肠癌的新辅助放射治疗已被证明能有效地降低患者术前肿瘤分期、改善患者生存以及降低直肠癌局部复发率等,随之而来的是患者放疗后出现的不同程度的放疗不良反应,但随着放射治疗规范化、放射治疗技术及设备的改进,放疗不良反应严重程度在逐渐降低。本文就新辅助放疗中的放疗方案的选择、放射治疗技术、放疗不良反应、放疗后的手术时间以及放疗后的观察与等待等问题的最新研究进展进行了系统性的综述,从而为临床直肠癌新辅助治疗提供有力依据。     

Long-term quality-of-life after neoadjuvant short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer

Purpose

To evaluate long-term quality-of-life (QoL) after neoadjuvant short-course radiotherapy (SC-RT) and long-course radiochemotherapy (LC-RCHT) for locally advanced rectal cancer.

Methods

Between 1999 and 2008, 225 patients were treated with curative intent for locally advanced rectal cancer using neoadjuvant SC-RT (n = 108) or LC-RCHT (n = 117). SC-RT delivered 10 × 2.9 Gy twice daily with immediate surgery. LC-RCHT delivered 28 × 1.8 Gy concomitant with 5-FU based chemotherapy and delayed surgery. A cross-sectional QoL analysis was performed in disease-free patients using the EORTC-QLQ-C30 and EORTC-QLQ-CR29 questionnaires.

Results

After a median follow-up of 67 months, 133 patients were disease-free of which 120 (90%) returned the QoL questionnaires. Patients in the LC-RCHT cohort had a higher rate of uT4, uN+ and low tumor location. No difference in QoL was observed between SC-RT and LC-RCHT except an improved physical functioning in the LC-RCHT group (p = 0.04). Comparing our total patient cohort with the general German population showed no difference in global health status but decreased QoL in several functional and bowel symptom scores.

Conclusions

The finding of comparable long-term QoL after SC-RT and LC-RCHT adds to our knowledge of equivalent oncological outcome and may be useful in the decision making process between the two neoadjuvant approaches.     

Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer

BACKGROUND

Toxicity from neoadjuvant chemoradiation therapy (NT) increases morbidity and limits therapeutic efficacy in patients with rectal cancer. The objective of this study was to determine whether specific polymorphisms in genes associated with rectal cancer response to NT were correlated with NT‐related toxicity.

METHODS

One hundred thirty‐two patients with locally advanced rectal cancer received NT followed by surgery. All patients received 5‐fluorouracil (5‐FU) and radiation (RT), and 80 patients also received modified infusional 5‐FU, folinic acid, and oxaliplatin chemotherapy (mFOLFOX‐6). Grade ≥3 adverse events (AEs) that occurred during 5‐FU/RT and during combined 5‐FU/RT + mFOLFOX‐6 were recorded. Pretreatment biopsy specimens and normal rectal tissues were collected from all patients. DNA was extracted and screened for 22 polymorphisms in 17 genes that have been associated with response to NT. Polymorphisms were correlated with treatment‐related grade ≥3 AEs.

RESULTS

Overall, 27 of 132 patients (20%) had grade ≥3 AEs; 18 patients had a complication associated only with 5‐FU/RT, 3 patients experienced toxicity only during mFOLFOX‐6, and 6 patients had grade ≥3 AEs associated with both treatments before surgery. Polymorphisms in the genes x‐ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), xeroderma pigmentosum group D (XPD), and tumor protein 53 (TP53) were associated with grade ≥3 AEs during NT (P < .05). Specifically, 2 polymorphisms—an arginine‐to‐glutamine substitution at codon 399 (Q399R) in XRCC1 and a lysine‐to‐glutamine substitution at codon 751 (K751Q) in XPD—were associated with increased toxicity to 5‐FU/RT (P < .05), and an arginine‐to‐proline substitution at codon 72 (R72P) in TP53 was associated with increased toxicity to mFOLFOX‐6 (P = .008).

CONCLUSIONS

Specific polymorphisms in XRCC1, XPD, and TP53 were associated with increased toxicity to NT in patients with rectal cancer. The current results indicated that polymorphism screening may help tailor treatment for patients by selecting therapies with the lowest risk of toxicity, thus increasing patient compliance. Cancer 2013. © 2012 American Cancer Society.     

局部晚期直肠癌术前短程放疗的研究进展

术前放疗提高了局部晚期直肠癌的局部控制率,可以采用常规分割同步化疗的长程方案,也可行25 Gy／5次短程放疗。前者肿瘤反应率高;后者毒副反应低,耐受性好。二者局部控制率无差异,均好于单独手术,但总生存率未见提高。短程放疗延期4～8周后手术较7天内手术提高了肿瘤反应率。近期研究又发现短程放疗联合新辅助化疗并延期手术,进一步提高了肿瘤的完全缓解率,甚至有超过长程同步放化疗的趋势,局部控制率亦不劣于长程。但是否可降低远处转移率,提高总生存率还有待长期研究。     

直肠癌术前放疗的疗效观察

目的 观察直肠癌术前放疗的临床效果。方法 对28例直肠癌病人进行术前放疗，观察肿块变化情况，不良反应，进行术后随访等。结果 放疗后肿块缩小，保肛率提高、局部复发率降低。结论 术前放疗可以减少复发率，提高切除率，增加保肛率，为直肠癌综合治疗的较佳方式。     

p53 status and response to radiotherapy in rectal cancer: a prospective multilevel analysis

The aim of this study was to evaluate, in a prospective study, the predictive role of p53 status analysed at four different levels in identifying the response to preoperative radiotherapy in rectal adenocarcinoma. Before treatment, 70 patients were staged and endoscopic forceps biopsies from the tumour area were taken. p53 status was assessed by total cDNA sequencing, allelic loss analysis, immunohistochemistry, and p53 antibodies. Neoadjuvant treatment was based on preoperative radiotherapy or radiochemotherapy. Response to therapy was evaluated after surgery by both pathologic downstaging and histologic tumour regression grade. In all, 35 patients (50.0%) had p53 gene mutations; 44.4% of patients had an allelic loss; nuclear p53 overexpression was observed in 39 patients (55.7%); and p53 antibodies were detected in 11 patients (16.7%). In the multilevel analysis of p53 status, gene mutations correlated with both nuclear protein overexpression (P < 0.0001) and loss of heterozygosity (P = 0.013). In all, 29 patients (41.4%) were downstaged by pathologic analysis, and 19 patients (29.2%) were classified as tumour regression grade 1. Whatever the method of evaluation of treatment response, no correlation between p53 alterations and response to radiotherapy was observed. Our results do not support the use of p53 alterations alone as a predictive marker for response to radiotherapy in rectal carcinoma.     

调节性T细胞与肿瘤放疗

放射疗法（放疗）是当今治疗恶性肿瘤最常用的方法之一,中国肿瘤患者中约有70%接受放疗。放疗的免疫调节效应已经引起了极大的关注,越来越多的研究报道放疗和免疫治疗之间有很多协同之处。调节性Ｔ细胞(regulatory T cells,Treg)是一群具有免疫抑制性作用的细胞,与肿瘤关系密切,可通过细胞与细胞间接触、分泌抑制性的细胞因子以及干扰细胞代谢等方式参与到肿瘤的发病机制、进展以及肿瘤的治疗和预后等各个领域。该文以Treg的免疫学特性为出发点,系统的阐释肿瘤放疗与免疫分子的相互关系,旨在为肿瘤放疗联合Treg免疫治疗提供新的思路。     

Upfront chemotherapy and short-course radiotherapy with delayed surgery for locally advanced rectal cancer with synchronous liver metastases

BackgroundThe optimal treatment of locally advanced rectal cancer with synchronous liver metastases remains controversial. In this study, we aimed to evaluate the safety, efficacy, and oncologic outcomes of upfront chemotherapy and short-course radiotherapy with delayed surgery in patients with locally advanced rectal cancer and synchronous liver metastases.MethodsForty-four patients who underwent upfront chemotherapy and short-course radiotherapy with delayed surgery for locally advanced rectal cancer (cT3/4, <2.0 mm from the mesorectal fascia) with synchronous liver metastases between January 2010 and June 2017 were reviewed retrospectively. Primary and metastatic liver lesions were resected with curative intent. Upfront chemotherapy and short-course radiotherapy were administered. Thereafter, restaging, surgery only, or additional chemotherapy followed by surgery was performed.ResultsAt the time of initial diagnosis, 20 patients had <3 liver metastases; 24 patients had ≥3 liver metastases. Twenty-three patients had hemi-liver metastases; 21 patients had bilobar liver metastases. R0 resection of rectal lesions was achieved in 43 patients. Synchronous R0 resection of liver metastases was achieved in 41 patients. Postoperative complications (Clavien–Dindo Grade ≥ III) were noted in 5 patients. Grade 3/4 adverse events were observed in 26 patients. All adverse events were managed effectively with medication and supportive care. The 3-year overall survival and progression-free survival rates were 65.3% and 26.9%, respectively.ConclusionUpfront chemotherapy and short-course radiotherapy with delayed surgery appear to be safe and effective in patients with locally advanced rectal cancer and synchronous liver metastases without substantially increasing treatment induced morbidity.     

术前短程放疗对于直肠癌根治性切除术手术的安全性影响及远期疗效探讨

目的：观察术前短程放疗在直肠癌根治性切除术中的远期疗效及安全性。方法选取90例直肠癌患者,根据治疗方法的不同分为观察组（n=45）与对照组（n=45）。对照组患者采用直接性切除术治疗,观察组患者先行断层放疗后进行手术治疗,对两组患者的手术一般情况、远期疗效及术后安全性指标进行比较。结果两组患者的术前Ⅰ级和Ⅱ级不良反应发生率、平均手术时间、术中出血量、术后排气时间和平均住院时间比较,差异均无统计学意义（P﹥0.05）;观察组患者的术后并发症发生率低于对照组患者,差异无统计学意义（P﹥0.05）;观察组患者的淋巴结转移率、盆腔局部复发率均低于对照组患者（P﹤0.05）,3年生存率优于对照组患者（P﹤0.05）。结论直肠癌根治性切除术前进行短程放疗具有较好的安全性,且患者远期疗效明显优于单纯根治性切除术,具有较好的临床应用价值。     

直肠癌新辅助放化疗敏感性预测进展

直肠癌是我国最常见的恶性肿瘤之一。近年来,直肠癌的新辅助放疗或放疗联合化疗及全直肠系膜切除的根治术已逐步成为治疗中下段进展期直肠癌的标准模式。目前已经有大量研究证实新辅助治疗的优点,但尚有一部分患者无法在其中受益。在新辅助放化疗前或其早期预测其敏感性,达到肿瘤的“个体化治疗”,目前在这方面已经进行了大量研究。本文将就预测新辅助治疗敏感性的进展进行综述。     

Three-Dimensional Conformal Radiotherapy for Rectal Cancer and the Changes in Cancer Multi-biomarkers

OBJECTIVE To investigate the clinical efficacy of three-dimensional conformal radiotherapy(3D-CRT)for local y advanced or postoperatively relapsed rectal cancer,and to examine the changes in cancer multi-biomarkers. METHODS Sixty patients with locally advanced or postoperatively relapsed rectal cancer were randomly divided into two groups after 40 Gy external radiation,namely a late-course 3D-CRT group and a conventional radiotherapy group that served as the control.There were 30 patients in each group.For patients in the 3D-CRT group,multi-biomarkers were measured before and after radiotherapy and after relapse. RESULTS Response rates in the 3D-CRT and the control groups were 86.7%(26/30)and 70%(21/30)respectively,without a significant difference (P>0.05).The 1-,2-and 3-year survival rates were 80%,53.3%and 36.7% in the 3D-CRT group;in the control group the rates were 56.7%,40%and 13.3%respectively,with a significant difference(P=0.0213).CEA,CA19-9, CA242 and FER decreased after radiotherapy in the 3D-CRT group,P<0.01, indicating a significant difference.The values after relapse were higher than those without relapse,P<0.01,indicating a significant difference. CONCLUSION Conventional radiotherapy with a 3D-CRT boost gives better therapeutic effect to patients with locally advanced or postoperatively local y relapsed rectal cancer.A multi-biomarker protein chip diagnosis system can be utilized as an effective tool to determine the therapeutic effect and prognosis.     

肿瘤浸润淋巴细胞对直肠癌术前放疗预后的影响

目的 探讨直肠痛肿瘤组织内术前放疗后浸润淋巴细胞(TIL)数量改变对预后的影响.方法 搜集近8年余接受30 Gy分10次12 d完成的术前放疗的直肠癌患者107例,分析TIL分级与术前放疗后病理消退程度及预后关系.结果 直肠癌放疗前TIL 1级75例,2级16例,3级16例,4级0例,术前放疗后TIL 1级19例,2级43例,3级35例,4级10例.放疗后病理消退分级1级36例,2级57例,3级14例.单因素分析发现放疗前及放疗后TIL对局部病理消退影响有统计学意义(X2=36.80,P<0.01;X2=14.00,P<0.01);术前放疗后癌巢内TIL及病理消退对预后影响显著(X2=24.00,P<0.01;X2=12.17,P<0.01).Logistic多元分析提示放疗后TIL与病理消退关系密切(X2=8.05,P<0.01).结论 放疗前及放疗后TIL与直肠癌术前放疗局部病理消退相关.直肠癌术前放疗后癌巢TIL是影响生存预后的因素之一.     

Intermediate neoadjuvant radiotherapy for T3 low/middle rectal cancer: postoperative outcomes of a non-controlled clinical trial

Background

The benefits of adjuvant radiotherapy in rectal carcinoma are well known. However, there is still considerable uncertainty about the optimal radiation treatment. There is an ongoing debate about the choice between very short treatments immediately followed by surgical resection and prolonged treatments with delayed surgery. In this paper, we describe an interim analysis of a non-controlled clinical trial in which radiotherapy delivered with intermediate dose/duration was followed by surgery after about 2 weeks to improve local control and survival after curative radiosurgery for cT3 low/middle rectal cancer.

Methods

Preoperative radiotherapy (36 Gy in 3 weeks) was delivered in 248 consecutive patients with cT3NxM0 rectal adenocarcinoma within 10 cm from the anal verge, followed by surgery within the third week after treatment completion.

Results

166 patients (66.94%) underwent anterior resection, 80 patients (32.26%) the Miles'' procedure and 2 patients (0.8%) the Hartmann''s procedure. Local resectability rate was 99.6%, with 226 curative-intent resections. The overall rate of complications was 27.4%. 5-year oncologic outcomes were evaluated on 223 patients. The median follow-up time was 8.9 years (range 5-17.4 years); local recurrence (LR) rate and distal recurrence (DR) rate after 5 years were 6.28% and 21.97%, respectively. Overall survival was 74.2%; disease free survival was 73.5%; local control was 93.4 % and metastasis-free survival was 82.1%.

Conclusions

preoperative radiotherapy with intermediate dose/duration and interval between radiotherapy and surgery achieves high local control in patients with cT3NxM0 rectal cancer, and high DR rate seems to be the major limitation to improved survival.     

局部晚期低位直肠癌术前不同放疗模式疗效观察

目的：探讨术前不同放疗模式对局部晚期低位直肠癌的治疗意义。方法：40例局部晚期低位直肠癌患者,其中23例采用术前同步放化疗,放疗方式采用盆腔外照射,DT 50戈瑞/25次,化疗方案为卡培他滨750毫克/米2,每日两次口服,间隔12小时,连用5周,照射结束后4周手术。另17例患者采用短程低分割放疗方案,DT 25戈瑞/5次/5天,照射结束后1周左右手术。结果：术前同步放化疗组和术前短程低分割组有效率分别为78.2%和58.8%,保肛率分别为73.9%和44.4%,病理完全消失率分别为13.0%和0,3年生存率分别为73.9%和58.8%,P〈0.05,均有统计学差异。术后吻合口瘘发生率分别为4.3%和4.1%,P〉0.05无统计学差异。结论：局部晚期低位直肠癌术前同步放化疗临床疗效好,生存质量高,为优先选择方案。