The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma

OBJECTIVE: To investigate the efficacy of preoperative short-term radiotherapy in patients with mobile rectal cancer undergoing total mesorectal excision (TME) surgery. SUMMARY BACKGROUND DATA: Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 6 years. METHODS: One thousand eight hundred and sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 x 5 Gy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control. RESULTS: Median follow-up of surviving patients was 6.1 year. Five-year local recurrence risk of patients undergoing a macroscopically complete local resection was 5.6% in case of preoperative radiotherapy compared with 10.9% in patients undergoing TME alone (P < 0.001). Overall survival at 5 years was 64.2% and 63.5%, respectively (P = 0.902). Subgroup analyses showed significant effect of radiotherapy in reducing local recurrence risk for patients with nodal involvement, for patients with lesions between 5 and 10 cm from the anal verge, and for patients with uninvolved circumferential resection margins. CONCLUSIONS: With increasing follow-up, there is a persisting overall effect of preoperative short-term radiotherapy on local control in patients with clinically resectable rectal cancer. However, there is no effect on overall survival. Since survival is mainly determined by distant metastases, efforts should be directed towards preventing systemic disease.     

Total mesorectal excision in the treatment of rectal cancer: a review

Despite the improvements in preoperative staging, surgical technique and adjuvant therapy, local recurrence remains a significant problem in rectal cancer surgery. Several patient- and tumour-related risk factors for the development of local recurrence have been identified and are being addressed by regimens of pre- or postoperative adjuvant therapy. Total mesorectal excision (TME) recently has been shown to result in a low recurrence rate even without the use of adjuvant therapy. Nevertheless, conclusive evidence in the form of a prospective randomized trial is to date not available. This paper describes the technique of TME and reviews the clinical and pathological data supporting its use in rectal cancer surgery.     

术前放疗联合全直肠系膜切除术治疗可切除性直肠癌临床疗效的系统评价

目的评价术前放疗联合全直肠系膜切除术（TME）治疗局部可切除直肠癌的临床疗效。方法全面检索1982年1月至2009年4月间发表的评价术前放疗的前瞻性临床随机对照试验研究,按纳入和排除标准筛选,提取人选试验的基本特征和临床疗效数据。对研究目的相同的多项随机对照试验的临床数据采用RevMan4．2软件进行定量合并．对不符合定量合并要求的数据作统计描述。结果符合选择标准的临床随机对照试验9项。短程术前放疗联合规范的TME手术组治疗直肠癌的2年局部复发率为2．4％,低于单纯TME手术组的8．2％（P〈0．01）。术前放疗患者的4年总生存率和无病生存率与术前常规分割放化疗患者相比,差异无统计学意义（P〉0．05）：两组患者的局部复发率差异也无统计学意义（RR=1．16,95％C10．37～3．61,P=0．80）。术前高剂量放疗组完全缓解率显著高于低剂量组（16．0％比2．0％,P〈0．05）．保肛手术率提高3．9％。结论TME术前放疗可降低直肠癌术后局部复发的风险。     

Comparative outcome between chemoradiotherapy and lateral pelvic lymph node dissection following total mesorectal excision in rectal cancer

OBJECTIVE: To evaluate comparative outcome between adjuvant postoperative chemoradiotherapy (postoperative CRT) and lateral pelvic lymph node dissection (LPLD) following total mesorectal excision (TME) in rectal cancer patients. BACKGROUND: Although TME results in lower rate of locoregional recurrence compared with conventional surgery, these 2 treatment modalities following TME have not adequately been appraised until the present trend of preoperative chemoradiotherapy. PATIENTS AND METHODS: Between 1995 and 2000, patients with stage II and III rectal cancer underwent TME plus postoperative CRT (n = 309) or LPLD (n = 176). Patients in the postoperative CRT group received 8 cycles of 5-fluorouracil plus leucovorin and 45 Gy pelvic radiotherapy. Patients in the LPLD group underwent lateral lymph node dissection outside the pelvic plexus. RESULTS: The 5-year overall and disease-free survival rates were 78.3% and 67.3% in the postoperative CRT group, respectively, and 73.9% and 68.6% in the LPLD group, respectively, without significant differences between these groups. Patients in the LPLD group with stage III lower rectal cancer had a locoregional recurrence rate 2.2-fold greater than those in the postoperative CRT group (16.7% vs. 7.5%, P = 0.044). Multivariate analysis showed that APR and advanced T-category (T4) were significantly associated with locoregional recurrence, whereas lymph node metastases, high preoperative serum carcinoembryonic antigen, and APR were significantly associated with shortening of disease-free survival. CONCLUSIONS: Postoperative-CRT and LPLD following TME resulted in comparable survival rates, but the locoregional recurrence rate was higher in the LPLD group. These findings suggest that initial surgery is appropriate for rectal cancer patients who are candidates for low anterior resection without extensive local disease (T1-T3), regardless of lymph node status.     

Lymphovascular Invasion is a Significant Prognosticator in Rectal Cancer Patients Who Receive Preoperative Chemoradiotherapy Followed by Total Mesorectal Excision

Purpose  

This study was designed to identify the significance of lymphovascular invasion as a prognosticator for tumor recurrence and survival in rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME).     

经肛门局部切除手术在直肠癌治疗中的作用

直肠癌的外科手术方法包括经腹根治术及局部切除术。全直肠系膜切除术（TME）是直肠癌外科治疗的金标准．随着功能外科时代的到来．越来越多的证据表明．在严格选择适应证的前提下．早期直肠癌患者行局部切除手术可以获得和传统经腹根治术相同的生存率。但总体而言．局部切除术后的局部复发率要高于TME．因此需要术前做到全面、精确的分期和评估．从而严格掌握局部切除的手术适应证。     

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??Management of complete response after neoadjuvant chemoradiotherapy in rectal cancer SU Xiang-qian, YANG Hong. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)??Department of Minimally Invasive Gastrointestinal Surgery??Peking University Cancer Hospital & Institute??Beijing 100142??China
Corresponding author: SU Xiang-qian??E-mail: suxiangqian@bjmu.edu.cn
Abstract Neoadjuvant chemoradiotherapy (CRT) followed by radical surgery including total mesorectal excision (TME) is standard treatment in patients with locally advanced rectal cancer. The benefits of neoadjuvant CRT have been well documented and include tumor regression and downstaging associated with increased tumor respectability, reduced local recurrence and a higher rate of sphincter preservation. Radical surgery for rectal cancer carries a high risk of morbidity and mortality and can also greatly detract from a patient’s quality of life. In light of the significant response rates that can be achieved with preoperative CRT, some scholars have suggested limiting further surgical therapy to local excision alone or to observation for patients with clinical complete response (cCR). This article summarizes the latest development of management strategies for complete responders after neoadjuvant CRT for rectal cancer.     

Preoperative chemoradiation and extended pelvic lymphadenectomy for rectal cancer: Two distinct principles

Extended pelvic lymphadenectomy (EPL) with total mesorectal excision (TME) has been reported to provide oncological benefit in lower rectal cancer in Japan. In Western countries EPL is not widely accepted because of frequent morbidity but instead preoperative chemoradiation (CRT) followed by TME has been established as a standard treatment for decreasing local recurrence. Recently, several studies have focused on the comparison between these two distinct therapeutic approaches in Western countries and Japan. A study comparing Dutch trial data and Japanese data revealed that EPL and RT are almost equivalent in decreasing local recurrence in lower rectal cancer as compared with TME alone. Considering that almost 45% survival can be achieved by EPL even in the presence of metastatic lateral lymph nodes (LLNs), EPL performed by experienced surgeons definitely contributes to decrease local recurrence. On the other hand, a randomized controlled trial in Japan that compared EPL with conventional TME following preoperative RT revealed that EPL is associated with a higher frequency of sexual and urinary dysfunction without oncological benefits in the presence of preoperative RT. On this point, preoperative CRT followed by conventional TME without EPL would be a better therapeutic approach in patients without evident metastatic LLNs. For future treatment, it would be desirable to have a narrower indication for EPL using full advantage of recent improvement in image diagnosis. Although objective comparison of these two principles between Japan and the West is difficult due to differences in patient groups, further studies would lead to the next great step towards future improvement in treating lower rectal cancer.     

Factors that influence the adequacy of total mesorectal excision for rectal cancer

OBJECTIVE: In 1997 with the start of CRO7 trial it was agreed that adequacy of surgical resection of rectal cancer would be determined by a pathologically determined grading of the mesorectum the so called total mesorectal excision score (TME score). Scores ranged from 1-3 with 3 being a perfect specimen. The aim of this study was to investigate factors which may influence TME scores and establish if local recurrence is related to them. METHOD: Data on all patients undergoing resectional surgery for rectal cancer in our unit are entered prospectively onto a database. Pathology reports of those patients who underwent total mesorectal excision were examined and the TME scores added to the database. Categorical variables were analysed using the chi2 test, continuous variables using ANOVA. Statistical significance was taken as P < 0.05. RESULTS: Between January 2000 and June 2005, 518 patients underwent surgery for adenocarcinoma of the rectum, of these, 287 patients had a total mesorectal excision for mid or lower third tumours under the care of seven colorectal surgeons. All resected specimens were scored by a Consultant GI pathologist. Two hundred and fourteen patients underwent anterior resection and 73 underwent abdomino-perineal resection. The median age of the patients was 73 years (range 38-95 years). One hundred and ninety-four patients were male. Seventy-eight patients were treated with preoperative radiotherapy, 59 short course and 19 long course. TME scores were TME1 n = 30, TME2 n = 99, TME3 n = 158. Fifteen patients developed local pelvic recurrence at 2 years. Total mesorectal excision scores were not statistically influenced by Dukes' stage, width of tumour, preoperative radiotherapy or grade of surgeon. Male patients were statistically more likely to have a TME score of 2 or 3 compared with female P = 0.04. Patients undergoing an anterior resection were statistically more likely to have a TME score of 2 or 3 compared with abdomino-perineal resection P = 0.0001.Tumours with a circumferential resection margin (CRM) of more than 1 mm were more likely to have a TME score of 2 or 3 score (P = 0.0001). There was no relationship between TME and local recurrence (P = 0.966). CONCLUSION: There is no relationship between the TME score in patients undergoing resectional surgery for adenocarcinoma of the rectum and the development of local recurrence at 2 years. Other factors such as CRM involvement are more likely to have an impact on local recurrence. The factors that influence the quality of TME are the operative procedure of anterior resection, male gender and CRM positivity. There appear to be no deleterious effects on the TME score by Specialist Registrars performing the operation under Consultant supervision. While TME scores may be an index of a technical performance, they appear to have little role in predicting future outcomes.     

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??Management of clinical complete response after neoadjuvant chemoradiotherapy in low rectal cancer LUO Shuang-ling??KANG Liang. Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen Universiry,Guangzhou 510655,China
Corresponding author: KANG Liang,E-mail: eonkang@163.com
Abstract Neoadjuvant chemoradiotherapy ??CRT?? followed radical surgery including total mesorectal excision ??TME?? is standard treatment in patients with locally advanced rectal cancer. The benefits of neoadjuvant CRT have been well documented and include tumor regression and downstaging associated with increased tumor respectability??reduced local recurrence and a higher rate of sphincter preservation. Radical surgery for rectal cancer carries a high risk of morbidity and mortality and can also greatly detract from a patient’s quality of life. In light of the significant response rates that can be achieved with preoperative CRT??some scholars have suggested limiting further surgical therapy to local excision or just wait and see. Recently?? several studies have explored the feasibility and efficacy of organ-preserving strategies for low rectal cancer. Therefore?? it’s a new challenge for clinician to choose how to treat the situation with clinical complete response after neoadjuvant therapy for low rectal cancer patients.     

Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: not one millimeter but two millimeters is the limit

Despite improved surgical treatment strategies for rectal cancer, 5-15% of all patients will develop local recurrences. After conservative surgery, circumferential resection margin (CRM) involvement is a strong predictor of local recurrence. The consequences of a positive CRM after total mesorectal excision (TME) have not been evaluated in a large patient population. In a nationwide randomized multicenter trial comparing preoperative radiotherapy and TME versus TME alone for rectal cancer, CRM involvement was determined according to trial protocol. In this study we analyze the criteria by which the CRM needs to be assessed to predict local recurrence for nonirradiated patients (n = 656, median follow-up 35 months). CRM involvement is a strong predictor for local recurrence after TME. A margin of < or = 2 mm is associated with a local recurrence risk of 16% compared with 5.8% in patients with more mesorectal tissue surrounding the tumor (p <0.0001). In addition, patients with margins < or = 1 mm have an increased risk for distant metastases (37.6% vs 12.7%, p <0.0001) as well as shorter survival. The prognostic value of CRM involvement is independent of TNM classification. Accurate determination of CRM in rectal cancer is important for determination of local recurrence risk, which might subsequently be prevented by additional therapy. In contrast to earlier studies, we show that an increased risk is present when margins are < or = 2 mm.     

New approaches in the management of rectal carcinoma result in reduced local recurrence rate and improved survival.

OBJECTIVE: To find out whether total mesorectal excision (TME) technique alone or combined with preoperative radiotherapy reduces local recurrence rate and improves survival. DESIGN: Partly retrospective (the first period), partly prospective (the second period) study. SETTING: University hospital, Helsinki, Finland. SUBJECTS: 144 patients between 1980 and 1990 and 61 patients between 1991 and 1997 with rectal cancer, who underwent major curative surgery. Interventions: A conventional surgical technique was used during the first period and TME alone or combined with preoperative radiotherapy when appropriate during the second period. MAIN OUTCOME MEASURES: Postoperative morbidity and mortality, local recurrence rate, and 5-year survival. RESULTS: After anterior resection 4/76 of the patients (5%) during the first period and 8/43 (19%) during the second period developed anastomotic leaks. Operative 30-day mortality was 1% (n = 1) and 0, respectively. Actuarial local recurrence rate was 17% in the first period and 9% in the second period. Actuarial crude 5-year survival improved from 55% to 78% and cancer-specific survival from 67% to 86% between the two study periods. CONCLUSIONS: Despite an increased number of anastomotic complications TME is safe. Refinement of the surgical technique together with preoperative radiotherapy yields lower local recurrence rates and an improved survival compared with conventional surgery alone.     

Preoperative radiotherapy improves survival for patients undergoing total mesorectal excision for stage T3 low rectal cancers

OBJECTIVE: To examine the effect of preoperative radiotherapy (PRT) on patients who undergo rectal resection with total mesorectal excision (TME) for stage T3 low rectal cancers. SUMMARY BACKGROUND DATA: Evidence for the value of PRT before rectal cancer surgery is weakened by variability in the use of TME. Many surgeons have concluded that PRT is unnecessary for small rectal tumors if TME is performed, but there are no prospective data to support this opinion. METHODS: Since 1980, 2,200 patients with rectal cancer have been enrolled in a prospective database. Of these, 259 underwent curative anterior or abdominoperineal resection with TME for pathologically confirmed T3 lesions within 8 cm of the anal verge. Patients were grouped by receiving PRT (n = 92) or not receiving PRT (n = 167). Five-year overall survival and 5-year local recurrence rates were evaluated. RESULTS: Overall survival was increased from 52% in patients not receiving PRT to 63% in those receiving PRT. PRT increased overall survival for node-negative patients from 58% to 82%, with no benefit for node-positive patients. There was no significant difference in local recurrence rates. When categorized by tumor size, there was no difference in overall survival or local recurrence for 0- to 2-cm tumors or those larger than 5 cm, but PRT increased overall survival from 50% to 72% for patients with 2- to 5-cm tumors. Similar results were observed for patients with tumors staged as T3 on preoperative endoluminal ultrasound. CONCLUSIONS: Patients with pT3 low rectal cancers undergoing resection with TME have an improved survival with PRT. The effect is most beneficial for patients with node-negative and 2- to 5-cm tumors, although this group may include larger and node-positive tumors that have been downstaged by PRT. PRT should be advocated for all patients with T3 rectal cancers less than 8 cm from the anal verge, even if the surgery includes a properly performed TME.     

Modern rectal cancer surgery—Total mesorectal excision—The standard of care

The literature has repeatedly shown the superiority of total mesorectal excision (TME) for rectal cancer in reducing the incidence of local recurrence (LR) and improving long-term survival compared to conventional blunt rectal dissection. This article reviews the history of surgery for rectal cancer, supports TME as the standard of care in obtaining a negative circumferential margin (CRM) for mid- and lower-third rectal cancers, discusses the drawbacks of TME, the role of tumor-specific mesorectal excision for upper-third rectal cancers and laparoscopic TME, and emphasizes the need for a selective role of chemoradiation with TME for rectal cancer. The need for standardizing TME in the United States with pathological specimen quality analysis and reporting of the completeness of the TME specimen is also emphasized.     

Selective Lateral Pelvic Lymph Node Dissection in Patients with Advanced Low Rectal Cancer Treated with Preoperative Chemoradiotherapy Based on Pretreatment Imaging

Background

The significance of lateral pelvic lymph node (LPLN) metastasis in advanced low rectal cancer treated with preoperative chemoradiotherapy (CRT) remains unclear. The objective of this study was to evaluate the outcomes of selective LPLN dissection (LPLD) based on the pretreatment imaging in patients with advanced low rectal cancer treated with preoperative CRT.

Methods

We reviewed 127 consecutive patients with clinical stage II–III low rectal cancer below the peritoneal reflection who underwent preoperative CRT and curative resection. LPLD was performed in patients with suspected LPLN metastasis based on MDCT or MRI before CRT (LPLD group, N = 38), and only total mesorectal excision (TME) was performed in patients without suspected LPLN metastasis (TME group, N = 89). Clinical characteristics and the oncological outcome were compared between groups.

Results

The median tumor-to-anal verge distance was 40 mm in both groups. The median maximum long-axis LPLN diameter before CRT was 0 mm in the TME group and 10.5 mm in the LPLD group. Pathological LPLN metastasis was confirmed in 25 patients (66 %) in the LPLD group. Local recurrence at LPLN developed in 3 patients (3.4 %) in the TME group and in none (0 %) of the LPLD group. Multivariate analysis showed that only ypN was an independent prognostic factor for relapse-free survival (RFS), but LPLN metastasis was not associated with poor RFS.

Conclusions

The incidence of LPLN metastasis is high even after preoperative CRT, and LPLD might improve local control and survival of patients with LPLN metastasis in advanced low rectal cancer treated with preoperative CRT.     

Low rates of local recurrence after surgical resection of rectal cancer suggest a selective policy for preoperative radiotherapy

Aim Preoperative short‐course radiotherapy (SCRT) is increasingly recommended to reduce local recurrence after surgery for rectal cancer. Its avoidance may be beneficial, however, if the risk of local recurrence is low. We report a single centre experience which suggests that selective rather than uniform use of SCRT may be the best approach. Method Analysis was carried out on a prospectively collected unselected series of 1606 patients with rectal cancer treated in one centre. Follow‐up was 97% complete. SCRT was performed selectively and all patients had a mesorectal excision. Results Among 940 patients undergoing a potentially curative major resection the operative mortality was 4.6%, the permanent stoma rate 23% and the crude 5‐year survival 61%. The local recurrence rate after curative anterior resection was 2.9% and 7.7% after abdominoperineal excision. The overall local recurrence rate after a potentially curative major resection was 4.0%. Conclusion The routine use of preoperative radiotherapy for rectal cancer is probably not justified where local recurrence after curative rectal resection is uncommon.     

Total mesorectal excision with autonomic nerve preservation: a new foundation for the evaluation of multi-disciplinary adjuvant therapy in the management of rectal cancers

Local and distant recurrence rates and disease-free and overall survival are markedly improved by total mesorectal excision, with little increase in morbidity, compared with other techniques of resection of rectal cancer. Adjuvant therapy is associated with significant morbidity and initial results suggest it may not be beneficial in the aggregate. Adjuvant therapy must be re-evaluated in trials using TME as standard operative technique. Different subgroups of patients, defined by clinical and pathological criteria will be best served by different forms of therapy and should be studied based on rates of local and distant recurrence. Selected groups of patients will be best served by undergoing no adjuvant therapy of any kind.     

Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands

BACKGROUND: Local control and survival following surgical treatment of rectal cancer have been improved by the introduction of total mesorectal excision (TME). The aim of this study was to determine the nationwide impact of the introduction and training of TME on recurrence and survival in rectal cancer. METHODS: Short- and long-term outcomes of a recently published trial of rectal cancer surgery (TME trial) were compared with results from an older trial (cancer recurrence and blood transfusion (CRAB) trial), in which conventional surgery was performed without quality control. Only patients who were operated on with curative intent and who did not receive neoadjuvant radiotherapy were studied. Differences in clinicopathological characteristics were corrected for by multivariate analysis. To ensure valid comparisons, only events that occurred within 2 years of operation were analysed with regard to long-term outcome. RESULTS: In the univariate analysis, a higher clinical anastomotic leak rate was found in patients following low anterior resection in the TME trial (P = 0.046), but this association was not significant in the multivariate analysis. The local recurrence rate decreased from 16 per cent in the CRAB trial to 9 per cent in the TME trial, and type of operation (conventional (CRAB trial) versus TME (TME trial)) was an independent predictor of local recurrence (P = 0.002). Type of operation was also an independent predictor of overall survival (P = 0.019); there was a higher survival rate in the TME trial. CONCLUSION: The introduction and training of TME has led to improved long-term outcome of patients with rectal cancer in the Netherlands.     

Long-Term Outcome of Patients with Complete Pathologic Response after Neoadjuvant Chemoradiation for cT3 Rectal Cancer: Implications for Local Excision Surgical Strategies

Background

Neoadjuvant chemoradiotherapy (CRT) followed by radical surgery including total mesorectal excision (TME) is standard treatment in patients with locally advanced rectal cancer. Emerging data indicate that patients with complete pathologic response (ypCR) after CRT have favorable outcome, suggesting the possibility of less invasive surgical treatment. We analyzed long-term outcome of cT3 rectal cancer treated by neoadjuvant CRT in relation to ypCR and type of surgery.

Methods

The study population comprised 139 patients (93 men, 46 women; median age 62 years) with cT3N0–1M0 mid and distal rectal adenocarcinoma treated by CRT and surgery (110 TME and 29 local excision) at our institution between 1996 and 2008. At pathology, ypCR was defined as no residual cancer cells in the primary tumor.

Results

Tumors of 42 patients (30.2%) were classified as ypCR. After a median follow-up of 55.4 months, comparing patients with ypCR to patients with no ypCR, 5-year disease-specific survival was 95.8% versus 78.0% (P = 0.004), and 5-year disease-free survival was 90.1% vs. 64.0% (P = 0.004). In patients with ypCR, no statistically significant outcome difference was observed between TME and local excision. In patients treated by local excision, comparing patients with ypCR to patients with no ypCR, 5-year disease-free survival was 100% vs. 65.5% (P = 0.024), and 5-year local recurrence-free survival was 92.9% vs. 66.7% (P = 0.047).

Conclusions

With retrospective analysis limitations, our data confirm favorable long-term outcome of cT3 rectal cancer with ypCR after CRT and warrant clinical trials exploring local excision surgical strategies.     

全直肠系膜切除治疗直肠癌

目的 介绍全直肠系膜切除治疗直肠癌的手术方法及治疗效果。方法 文献综述。结果 采用全直肠系膜切除方法治疗直肠癌,其局部复发率由２０％～３０％下降至３％～８％,５年生存率达７５％,并使保肛机率增加。结论 直肠癌手术中采用全直肠系膜切除能降低直肠癌患者局部复发率,提高生存率,改善生存质量,值得推广。