Total Mesorectal Excision Trial Research Articles

Abandonment of Routine Radiotherapy for Nonlocally Advanced Rectal Cancer and Oncological Outcomes

Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. The main outcomes were 4-year local recurrence and overall survival rates. Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P = .99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P < .001), with lower non-cancer-related mortality (13.8% vs 6.3%; P < .001). The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally advanced rectal cancer did not compromise cancer-related outcomes at a national level. Optimizing clinical staging and surgery following the Dutch total mesorectal excision trial has potentially enabled safe deintensification of treatment.

Feasibility of Implementing the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events in a Multicenter Trial: NCCTG N1048.

Purpose The US National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to enable patient reporting of symptomatic adverse events in oncology clinical research. This study was designed to assess the feasibility and resource requirements associated with implementing PRO-CTCAE in a multicenter trial. Methods Patients with locally advanced rectal cancer enrolled in the National Cancer Institute-sponsored North Central Cancer Treatment Group (Alliance) Preoperative Radiation or Selective Preoperative Radiation and Evaluation before Chemotherapy and Total Mesorectal Excision trial were asked to self-report 30 PRO-CTCAE items weekly from home during preoperative therapy, and every 6 months after surgery, via either the Web or an automated telephone system. If participants did not self-report within 3 days, a central coordinator called them to complete the items. Compliance was defined as the proportion of participants who completed PRO-CTCAE assessments at expected time points. Results The prespecified PRO-CTCAE analysis was conducted after the 500th patient completed the 6-month follow-up (median age, 56 years; 33% female; 12% nonwhite; 43% high school education or less; 5% Spanish speaking), across 165 sites. PRO-CTCAE was reported by participants at 4,491 of 4,882 expected preoperative time points (92.0% compliance), of which 3,771 (77.2%) were self-reported by participants and 720 (14.7%) were collected via central coordinator backup. Compliance at 6-month post-treatment follow-up was 333 of 468 (71.2%), with 122 (26.1%) via backup. Site research associates spent a median of 15 minutes on PRO-CTCAE work for each patient visit. Work by a central coordinator required a 50% time commitment. Conclusion Home-based reporting of PRO-CTCAE in a multicenter trial is feasible, with high patient compliance and low site administrative requirements. PRO-CTCAE data capture is improved through centralized backup calls.

Objective assessment of minimally invasive total mesorectal excision performance: a systematic review.

Laparoscopy is widely used in colorectal practice, but recent trial results have questioned its use in rectal cancer resections. Patient outcomes are directly linked to the quality of total mesorectal excision (TME) specimen. Objective assessment of intraoperative performance could help ensure competence and delivery of optimal outcomes. Objective tools may also contribute to TME intervention trials, but their nature, structure and utilisation is unknown. To systemically review the available literature to report on the available tools for the objective assessment of minimally invasive TME operative performance and their use within multicentre laparoscopic TME randomised controlled trials. A systematic search of the PubMed and Cochrane databases was performed to identify tools used in the objective intraoperative assessment of minimally invasive TME performance in accordance with the PRISMA guidelines, independently by two authors. The identified tools were then evaluated within reported TME RCTs. A total of 8642 abstracts were screened of which 12 papers met the inclusion criteria; ten prospective observational studies, one randomised trial and one educational consensus. Eight assessment methods were described, which include formative and summative tools. The tools were mostly adaptations of colonic surgery tools based on either operative video review or post-operative trainer rating. All studies reported objective assessment of intraoperative performance was feasible, but only 126 (7%) of the 1762 included laparoscopic cases were TME. No multicentre laparoscopic TME trial reported using any objective surgical performance assessment tool. Objective intraoperative laparoscopic TME performance assessment is feasible, but most of the current tools are adaptation of colonic surgery. There is a need to develop dedicated assessment tools for minimal access rectal surgery. No multicentre minimally invasive TME RCT reported using any objective assessment tool.

Should the Benefit of Adjuvant Chemotherapy in Colon Cancer Be Re-Evaluated?

Because favorable effects on survival were seen in randomized trials conducted during the 1980s, adjuvant chemotherapy in colon cancer was established as routine therapy in stage III disease in the United States in 1990. Follow-up trials in the United States, Asia, and Europe soon meant that it became recommended therapy worldwide, not only in stage III but in stage II disease as well, if risk factors for recurrence were present. Additional trials established the combination of a fluoropyrimidine and oxaliplatin as reference treatment for patients with stage II disease with risk factors who are fit for therapy and for those with stage III disease. The addition of oxaliplatin in the treatment of elderly patients has been questioned. Here we present arguments questioning not only the addition of oxaliplatin in the treatment of some younger patients as well but also the offering of adjuvant chemotherapy at all to some of these patients. Medical care continuously develops, and as a consequence, treatment results improve. This development has also been seen in colon (and rectal) cancer, and the improvements actually challenge the established benefit of adjuvant chemotherapy in colon (and rectal) cancer. We question whether the risk of recurrence is sufficiently high for most patients with stage II disease, even when risk factors are present, and for some patients with stage III disease in the presence of high-quality, modern, multidisciplinary team care to motivate adjuvant chemotherapy. In colorectal cancer, there has been a marked change during the past decades regarding surgery. It started with the total mesorectal excision (TME) technique for rectal cancer. This technique has now spread around the world; the majority of surgeons have learned how to operate effectively on rectal cancer, and many centers report low local recurrence rates. Population-based data from national quality registers also show that the local recurrence rate can today reach approximately 5%, equaling the rates achieved in dedicated centers. Surgery for colon cancer may also be about to change, with complete mesocolic excision dissection and the concept of central ligation. These techniques have started to spread among surgeons, and population data already indicate that there may be an overall survival benefit, in addition to improvements reflecting stage migration, if colonic surgery is performed in accordance with such procedures. Preoperative staging of colorectal cancer has also improved, and up-to-date contrast-enhanced computed tomography of the thorax and abdomen, completed with ultrasonography or magnetic resonance imaging with contrast agents in the case of equivocal liver lesions or positron emission tomography– computed tomography in the case of equivocal findings outside the liver, has also resulted in fewer recurrences in those undergoing surgery (ie, the target patients for adjuvant therapy). The scenario has changed from fewer metachronous to more synchronous metastases. Furthermore, although pathologists cannot reduce recurrence risks per se, better pathologic staging results in lower stage-specific recurrence rates, often referred to as stage migration. The rectal cancer radiotherapy story illustrates the same kind of problem the medical community is facing when one or several aspects of multidisciplinary care are improved. The story is well known from literature. The reduction in local recurrence rates seen after preoperative radiotherapy was questioned when surgery was improved (ie, when TME was introduced). The two trials then initiated—the Dutch–Swedish TME trial and the Medical Research Council CR07 trial in the United Kingdom, in which preoperative radiotherapy using the 5 3 5 Gy schedule was tested against selective postoperative (chemo)radiotherapy—showed that preoperative radiotherapy significantly reduced local recurrence rates. Actually, the relative reduction may have been slightly larger with TME (hazard ratio, 0.38; absolute difference, 11% v 4%) than with the older, suboptimal surgery (hazard ratio, 0.46; absolute difference, 27% v 13%). The overall survival gain seen previously in the Swedish Rectal Cancer Trial could not be reproduced; the absolute gain in local recurrences was likely too small to show up in the trials in which TME was used. The gains from postoperative chemoradiotherapy in local recurrence rates and survival have not been tested using TME. In a German trial testing preversus postoperative chemoradiotherapy, it was shown that preoperative chemoradiotherapy was better than postoperative in reducing the local recurrence rate, approximately 10% after postoperative treatment versus 7% after preoperative irradiation. The TME technique was used for most patients in the trial, but no difference in survival could be seen even after long-term follow-up. On the basis of this knowledge, there is an ongoing debate over whether radiotherapy is needed in the majority of rectal cancers because of the low recurrence rates seen today without

Long-Term Health-Related Quality of Life in Patients With Rectal Cancer After Preoperative Short-Course and Long-Course (Chemo) Radiotherapy

BackgroundBoth preoperative short-course radiotherapy (SC-PRT) and preoperative long-course chemo radiotherapy (CRT) have shown to reduce local recurrence rates after total mesorectal excision (TME), but neither resulted in improved survival. This study compared the long-term health-related quality of life (HRQL) and symptoms between CRT and SC-PRT. MethodsPatients who were preoperatively treated with a total dose of 50.0 to 50.4 Gy for locally advanced rectal cancers were identified from 2 hospital registries. Starting from 2011, all patients who were disease-free in the study population (n = 105) were sent a HRQL-questionnaire composed of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and questions on bowel and urinary function. Patients who underwent SC-PRT in the TME trial were used as a reference group. ResultsHRQL results from 85 patients receiving CRT (81.0%), with a median follow-up time of 58 months, were compared with the results of patients who underwent SC-PRT (n = 306). Apart from more nausea and vomiting reported by patients receiving CRT (mean score for CRT 5.9 vs. 1.3 for SC-PRT; P < .01; not clinically relevant) and less satisfaction with urinary function indicated by patients who received CRT (mean score for CRT 71.2 vs. 81.2 for SC-PRT; P < .01), no significant differences were found in HRQL and symptoms between patients who received CRT and SC-PRT. ConclusionsThis analysis of HRQL in patients who received CRT shows no clinically relevant differences in long-term HRQL and symptoms between patients who received CRT and SC-PRT, apart from less satisfaction with urinary function reported by patients who received CRT. These results indicate that both approaches have a comparable impact on long-term HRQL.

A comprehensive longitudinal overview of health-related quality of life and symptoms after treatment for rectal cancer in the TME trial

Background: Total mesorectal excision (TME) combined with preoperative short-term radiotherapy (PRT) reduces local recurrence rates in rectal cancer treatment. However, treatment with radiotherapy increased morbidity and did not result in a longer survival. The aim of this analysis is to provide a comprehensive longitudinal overview of the health-related quality of life (HRQL) and symptoms experienced by rectal cancer patients in the Dutch randomized TME trial from baseline until 14 years after treatment.Methods: Rectal cancer patients (n =1530) were randomly allocated to PRT (5 × 5 Gy) followed by TME or to TME alone. At baseline, 3, 6, 12, 18, and 24 months, 5 years and 14 years after treatment HRQL was evaluated in surviving patients (n =606, at 14 years after treatment).Results: None of the general symptoms differed significantly between PRT + TME and TME. However, in both treatment arms the general symptoms were increased at the diagnosis of rectal cancer, after surgery and by aging. With PRT + TME bowel symptoms were increased, specifically more fecal incontinence was reported at all time points, resulting in more use of pads for fecal incontinence (PRT + TME vs. TME at 5 years 51.5% vs. 30.5%, respectively, and at 14 years 56.4% vs. 37.1%, respectively).Conclusions: This longitudinal analysis shows that general symptoms in both groups are increased at the diagnosis of rectal cancer, after surgery and by aging, but not by RT. However, irradiated patients reported more bowel dysfunction at all time points.

Reduced Circumferential Resection Margin Involvement in Rectal Cancer Surgery: Results of the Dutch Surgical Colorectal Audit.

The circumferential resection margin (CRM) is a significant prognostic factor for local recurrence, distant metastasis, and survival after rectal cancer surgery. Therefore, availability of this parameter is essential. Although the Dutch total mesorectal excision trial raised awareness about CRM in the late 1990s, quality assurance on pathologic reporting was not available until the Dutch Surgical Colorectal Audit (DSCA) started in 2009. The present study describes the rates of CRM reporting and involvement since the start of the DSCA and analyzes whether improvement of these parameters can be attributed to the audit. Data from the DSCA (2009-2013) were analyzed. Reporting of CRM and CRM involvement was plotted for successive years, and variations of these parameters were analyzed in a funnelplot. Predictors of CRM involvement were determined in univariable analysis and the independent influence of year of registration on CRM involvement was analyzed in multivariable analysis. A total of 12,669 patients were included for analysis. The mean percentage of patients with a reported CRM increased from 52.7% to 94.2% (2009-2013) and interhospital variation decreased. The percentage of patients with CRM involvement decreased from 14.2% to 5.6%. In multivariable analysis, the year of DSCA registration remained a significant predictor of CRM involvement. After the introduction of the DSCA, a dramatic improvement in CRM reporting and a major decrease of CRM involvement after rectal cancer surgery have occurred. This study suggests that a national quality assurance program has been the driving force behind these achievements.

Modern Treatment of Rectal Cancer Closes the Gap Between Common Adenocarcinoma and Mucinous Carcinoma.

Mucinous carcinoma (MC) is a distinct form of rectal cancer (RC) comprising 10% of all cases and has been associated with an impaired prognosis compared with non-mucinous adenocarcinoma (AC). The benefit of today's modern treatment for MC patients is unknown but a prospective randomized trial to answer this does not seem feasible. This study provides an analysis of the modern treatment of rectal MC and efficacy of preoperative therapies for MC patients. Data from three large (trial) cohorts were used. Data from the Netherlands Cancer Registry (NCR) were used to analyze the prognosis of RC patients over time (N=38,035). To study the benefit of preoperative short-term radiotherapy, patients from the total mesorectal excision (TME) trial (N=1,530) were selected, and the benefit from preoperative chemoradiotherapy was analyzed with data on 540 locally advanced RC (LARC) patients from two hospitals. Data from the NCR confirmed that 5-year overall survival for MC was significantly worse from 1989 to 1998, but no longer different from AC from 1999 onwards. MC patients had a higher rate of positive circumferential resection margin than AC patients (TME trial 27.2 vs. 16.5%, p=0.006; LARC cohort 34.5 vs. 9.8%, p<0.0001), but there was no difference in outcome between MC and AC patients after preoperative short-term radiotherapy or chemoradiotherapy. Modern treatment of RC has benefited MC patients, leading to equal survival for MC and AC patients. Enhancements in the fields of imaging and quality of surgery have improved outcome and preoperative therapies should be recommended for both histological subtypes.

Bowel Function 14 Years After Preoperative Short-Course Radiotherapy and Total Mesorectal Excision for Rectal Cancer: Report of a Multicenter Randomized Trial

BackgroundWe investigated very long-term bowel function after total mesorectal excision (TME) with or without preoperative short-course radiotherapy (PRT) for rectal cancer, the risk factors for bowel dysfunction, and the association of bowel dysfunction with health-related quality of life (HRQL). Patients and MethodsIn the TME trial (1996-1999), 1530 Dutch patients with rectal cancer were randomized to TME preceded by 5 × 5 Gy PRT or TME alone. A set of questionnaires was sent to the surviving patients (n = 583) in 2012. The questionnaires included the Low Anterior Resection Syndrome Score (LARS score), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) and Colorectal Module (EORTC QLQ-CR29). The LARS score range was divided into “no LARS,” “minor LARS,” and “major LARS” categories in ascending severity of bowel dysfunction. The potential risk factors for major LARS were tested on multivariable analysis. The HRQL was compared between the LARS score categories. ResultsOf the 478 respondents, 242 nonstoma patients were included in the present analysis. The median interval since treatment was 14.6 years, and the median age at the follow-up point was 75 years. Major LARS was reported by 46% of all patients (56% PRT plus TME vs. 35% TME). PRT (odds ratio [OR], 3.0; 99% confidence interval [CI], 1.3-6.9) and age ≤ 75 years at the follow-up point (OR, 2.4; 99% CI, 1.1-5.5) increased the risk of major LARS. Gender, tumor height, anastomotic leakage, type of anastomosis, interval since treatment, and comorbid diabetes were not significant. Patients with major LARS fared worse in many HRQL domains (P < .01; score difference > 5% of score range). ConclusionA considerable proportion of nonstoma patients endured major LARS years after TME. PRT and age ≤ 75 years at follow-up pose further risks of major LARS in addition to surgery. Major LARS is associated with reduced HRQL.

Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: Report of a multicenter randomised trial

BackgroundPreoperative short-term radiotherapy (PRT) in combination with total mesorectal excision (TME) has shown to improve local control in rectal cancer treatment, however without a survival benefit and at the cost of increased morbidity. The current study investigates the long-term health-related quality of life (HRQL) of patients 14years after treatment in the Dutch TME trial. MethodsIn the TME trial (1996–1999) 1530 Dutch patients with rectal cancer were treated with TME and randomly assigned to PRT (5×5Gy). In 2012 HRQL was evaluated in surviving patients (n=606) using a questionnaire combining EORTC QLQ-C30, EORTC QLQ-CR29 and additional questions. FindingsResults were obtained from 478 patients (82%), with a median follow up of 14years. PRT+TME patients without stoma reported more faecal leakage and higher stool frequency, resulting in increased need of pads. Furthermore, irradiated males reported more erection problems. However, radiotherapy did not have negative effects on overall functioning. Compared with Dutch population, patients in both treatment arms reported a small decrease in overall functioning and males reported less sexual activity, interest and enjoyment and more erection difficulties. Irradiated females reported more vaginal dryness and more pain at intercourse compared with Dutch population. InterpretationLong-term HRQL evaluation shows that treatment-related symptoms are still present 14years after treatment for rectal cancer. Radiotherapy increased bowel dysfunction in patients without stoma. Compared with the Dutch population, both groups reported increased sexual dysfunction. Despite these treatment-related symptoms, there was no difference in overall functioning and global health between TME and PRT+TME.

Metastatic pattern in colorectal cancer is strongly influenced by histological subtype.

Clinical studies regarding colorectal cancer (CRC) have suggested differences in metastatic patterns between mucinous adenocarcinoma (MC), signet-ring cell carcinoma (SRCC) and the more common adenocarcinoma (AC). The current study systematically evaluates metastatic patterns of different histological subtypes in CRC patients and analyzes metastatic disease upon primary tumor localization. A nationwide retrospective review of pathological records of 5817 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA). To substantiate clinical relevance, metastatic patterns were compared with the prospective randomized multicenter Total Mesorectal Excision (TME) trial, which investigated efficacy of preoperative radiotherapy in rectal cancer patients. In the autopsy study, 1675 patients had metastatic disease. MC and SRCC patients more frequently had metastatic disease (33.9% and 61.2% versus 27.6%; P < 0.0001) and had metastases at multiple sites more often compared with AC patients (58.6% and 70.7% versus 49.9%; P = 0.001). AC predominantly metastasized to the liver, and MC and SRCC more frequently had peritoneal metastases. Metastatic patterns were also related to the primary tumor site, with a high rate of abdominal metastases in colon cancer patients, whereas rectal cancer patients more often had metastases at extra-abdominal sites. Results from the TME trial confirmed findings in rectal cancer patients from the autopsy study. There are profound differences in metastatic patterns between histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take these factors into account for follow-up strategies and future studies.

Quality Assurance in Rectal Cancer Treatment

Colorectal cancer is the cancer with the second highest cancer incidence in Europe. Roughly, 1 out of 3 patients with a colorectal malignancy has a rectal carcinoma. Surgery is the cornerstone in the curative treatment of rectal cancer. In the 1980s with conventional surgery, the 5-year local recurrence rate was over 20% and the 5-year overall survival rate around 50%. In the Swedish Rectal Cancer trial, in which 1,168 patients were included, preoperative radiotherapy in addition to conventional surgery resulted in a reduction of more than 50% in the 5-year local recurrence rate in comparison to conventional surgery alone (11 vs. 27%; p < 0.001). In addition, the 5-year overall survival rate improved from 48 to 58% if patients were treated with preoperative radiotherapy in addition to conventional surgery (p = 0.004). With total mesorectal excision (TME), by which the rectum with its mesorectum and visceral fascia are dissected sharply and under direct vision, local recurrence rates dropped and overall survival improved. In the Dutch TME trial, 5 × 5 Gy preoperative radiotherapy in combination with TME surgery was compared to TME surgery alone (1,861 patients). In this trial, the 5-year local recurrence rate for patients treated with TME surgery alone was similar to patients treated in the Swedish Rectal Cancer trial with blunt dissection in combination with preoperative 5 × 5 Gy radiotherapy (11%). If preoperative radiotherapy was added to TME surgery, the 5-year local recurrence rate was reduced to 5.6%. The overall survival rate at 5 years was 64% for both patients treated with TME surgery alone and patients treated with preoperative radiotherapy followed by TME surgery, compared to 48% for patients treated with blunt dissection alone in the previously mentioned Swedish trial. TME surgery is now considered the standard surgical procedure for rectal cancer. However, even if TME surgery is performed, surgical quality varies. First, these results indicate that improvements in the surgical procedure itself can result in major progress regarding long-term oncological outcome, such as decreased local recurrence rates and improved overall survival. Second, it illustrates that variation in surgical quality could lead to large differences in outcome. Recently, it was shown that surgical variation is not only important for patients with rectal cancer, but also plays an important role for the outcome of patients with colon cancer.

Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial

The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median follow-up of 12 years. Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 × 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection. 10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0·0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0·032). For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains. The Dutch Cancer Society, the Dutch National Health Council, and the Swedish Cancer Society.

…and a two-edged sword in their hands

Willem van Gijn and colleagues 1 van Gijn W Marijnen CAM Nagtegaal ID et al. for the Dutch Colorectal Cancer GroupPreoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011; (published online May 18.)https://doi.org/10.1016/S1470-2045(11)70097-3 Summary Full Text Full Text PDF Scopus (1146) Google Scholar report mature (10 year) results in terms of local recurrence and survival from the Dutch total mesorectal excision (TME) trial in rectal cancer. The trial had excellent quality assurance for surgery and pathology and, although many changes in staging and management have taken place since the original design, the results remain relevant today. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trialFor all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III. Full-Text PDF

Three-Dimensional Analysis of Recurrence Patterns in Rectal Cancer: The Cranial Border in Hypofractionated Preoperative Radiotherapy Can Be Lowered

The aim of this study was to determine whether and where the radiotherapy (RT) clinical target volume (CTV) could be reduced in short-course preoperative treatment of rectal cancer patients. Patients treated in the Dutch total mesorectal excision trial, with a local recurrence were analyzed. For 94 (25 who underwent radiation therapy 69 who did not) of 114 patients with a local recurrence, the location of the recurrence was placed in a three-dimensionalthree (3D) model. The data in the 3D model were correlated to the clinical trial data to distinguish a group of patients eligible for CTV reduction. Effects of CTV reduction on dose to the small bowel was tested retrospectively in a dataset of 8 patients with three-field conformal plans and intensity-modulated RT (IMRT). The use of preoperative RT mainly reduces anastomotic, lateral, and perineal recurrences. In patients without primary nodal involvement, no recurrences were found cranially of the S2-S3 interspace, irrespective of the delivery of RT. In patients without primary nodal involvement and a negative circumferential resection margin (CRM), only one recurrence was found cranial to the S2-S3 interspace. With a cranially reduced CTV to the S2-S3 interspace, over 60% reduction in absolute small bowel exposure at dose levels from 15 to 35 Gy could be achieved with three-field conventional RT, increasing to 80% when IMRT is also added. The cranial border of the CTV can safely be lowered for patients without expected nodal or CRM involvement, yielding a significant reduction of dose to the small bowel. Therefore, a significant reduction of acute and late toxicity can be expected.

Local excision of rectal cancer afterchemoradiation: feasibility depends on the primary stage

Local excision of rectal cancer afterchemoradiation: feasibility depends on the primary stage

Quality assurance in rectal cancer treatment in the Netherlands: A catch up compared to colon cancer treatment

Background In the Netherlands, the Total Mesorectal Excision (TME) surgical technique for rectal cancer was introduced together with pre-operative radiotherapy in a quality controlled manner within the framework of the TME trial (1996–1999). The aim of this study is to examine the effects of the structural changes in rectal cancer care on survival compared to colon cancer for patients treated before, during and after the TME trial. Method We compared overall survival of all patients with curatively resected colon ( n = 15,266) and rectal cancer ( n = 5839) in the regions of Comprehensive Cancer Centres South and West between 1990 and 2005, adjusting for prognostic variables. Results In the pre-trial period, rectal cancer had a significant lower survival compared to colon cancer (HR 1.248, P < 0.01). However, in the post-trial period, survival after rectal cancer was similar to colon cancer (HR 0.987, n.s.). Conclusion Although survival improved significantly for both colon and rectal cancer in the last 15 years, the substantially worse results after rectal cancer have been eliminated. This study shows the lasting effects that structural surgical training and quality assurance can have on survival outcome.

PIK3CA Mutations Predict Local Recurrences in Rectal Cancer Patients

Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly found in colon cancers, but their prevalence has not been clearly assessed in rectal cancer. In this study, we aim to determine the mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate whether a mutation may be used as a prognostic parameter in rectal cancer patients. We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in 240 stage I to III rectal tumors obtained from nonirradiated patients from the Dutch Total Mesorectal Excision trial. PIK3CA, KRAS, and BRAF mutations were identified in 19 (7.9%), 81 (33.9%), and 5 (2.1%) rectal cancers. Patients with PIK3CA mutations developed more local recurrences (5-year risks, 27.8% versus 9.4%; P = 0.006) and tended to develop these recurrences more rapidly after surgery (median local recurrence-free interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients without PIK3CA mutations. In multivariate analysis, PIK3CA mutations remained as an independent predictor for the development of local recurrences (hazard ratio, 3.4; 95% confidence interval, 1.2-9.2; P = 0.017), next to tumor-node-metastasis stage. PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Currently, our findings suggest that prospective evaluation of PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk patients who might otherwise only experience the side effects.

Developments in early rectal cancer treatment

Bowel cancer screening will change how rectal cancer presents. Data from the two UK pilots has shown that 49–62% of screen-detected tumours are ‘early’ (pT1–2N0M0; Stage I) [ 1 UK Flexible Sigmoidoscopy Screening Trial Investigators Single flexible sigmoidoscopy screening to prevent colorectal cancer: baseline findings of a UK multicentre randomised trial. Lancet. 2002; 359: 1291-1300 Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar , 2 UK Colorectal Cancer Screening Pilot Group Results of the first round of a demonstration pilot of screening for colorectal cancer in the United Kingdom. BMJ. 2004; 329: 133 Crossref PubMed Google Scholar ]. Radical total mesorectal excision (TME) offers high rates of cure for early rectal cancer; only 3–6% of patients subsequently relapse [ 3 Bentrem DJ Okabe S Wong WD et al. T1 adenocarcinoma of the rectum: transanal excision or radical surgery?. Ann Surg. 2005; 242: 472-477 PubMed Google Scholar , 4 Endreseth BH Myrvold HE Romundstad P Hestvik UE Bjerkeset T Wibe A Transanal excision vs. major surgery for T1 rectal cancer. Dis Colon Rectum. 2005; 48: 1380-1388 Crossref PubMed Scopus (188) Google Scholar , 5 Peeters KC Marijnen CA Nagtegaal ID et al. 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. Ann Surg. 2007; 246: 693-701 Crossref PubMed Scopus (896) Google Scholar ]. There are concerns, however, that radical surgery, which evolved to treat locally advanced, symptomatic tumours, may not be the optimal method of treatment for early (screen detected) tumours.

Die Rolle der Magnetresonanztomographie für die Indikationsstellung zur präoperativen Therapie beim Rektumkarzinom

Traditionally, the decision to apply preoperative treatment for rectal cancer patients has been based on the T- and N-category. Recently, the radial distance of the tumor to the circumferential resection margin (CRM) has been identified as an important risk factor for local failure. By magnetic resonance imaging (MRI) this distance can be measured preoperatively with high reliability. Thus, selected groups have started to limit the indication for preoperative therapy to tumors extending to - or growing within 1 mm from - the mesorectal fascia (CRM+). Pros and cons of this selected approach for preoperative treatment and first clinical results are presented. Prerequisites are the availability of modern high-resolution thin-section MRI technology as well as strict quality control of MRI and surgical quality of total mesorectal excision (TME). By selecting patients with CRM-positive tumors on MRI for preoperative therapy, only approximately 35% patients will require preoperative radiotherapy (RT) or radiochemotherapy (RCT). However, with histopathologic work-up of the resected specimen after primary surgery, the indication for postoperative RCT is given for a rather large percentage of patients, i.e., for pCRM+ (5-10%), intramesorectal or intramural excision (30-40%), pN+ (30-40%). Postoperative RCT, however, is significantly less effective and more toxic than preoperative RCT. A further point of concern is the assertion that patients, in whom a CRM-negative status is achieved by surgery alone, do not benefit from additional RT. Data of the Dutch TME trial and the British MRC (Medical Research Council) CR07 trial, however, suggest the reverse. To omit preoperative RT/RCT for CRM-negative tumors on MRI needs to be further investigated in prospective clinical trials. The German guidelines for the treatment of colorectal cancer 2008 continue to indicate preoperative RT/RCT based on the T- and N-category.