Koen C.M.J. Peeters

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 × 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.

Late Side Effects of Short-Course Preoperative Radiotherapy Combined With Total Mesorectal Excision for Rectal Cancer: Increased Bowel Dysfunction in Irradiated Patients—A Dutch Colorectal Cancer Group Study

PURPOSE Preoperative short-term radiotherapy improves local control in patients treated with total mesorectal excision (TME). This study was performed to assess the presence and magnitude of long-term side effects of preoperative 5 x 5 Gy radiotherapy and TME. Also, hospital treatment was recorded for diseases possibly related to late side effects of rectal cancer treatment. PATIENTS AND METHODS Long-term morbidity was assessed in patients from the prospective randomized TME trial, which investigated the efficacy of 5 x 5 Gy before TME surgery for mobile rectal cancer. Dutch patients without recurrent disease were sent a questionnaire. RESULTS Results were obtained from 597 patients, with a median follow-up of 5.1 years. Stoma function, urinary function, and hospital treatment rates did not differ significantly between the treatment arms. However, irradiated patients, compared with nonirradiated patients, reported increased rates of fecal incontinence (62% v 38%, respectively; P < .001), pad wearing as a result of incontinence (56% v 33%, respectively; P < .001), anal blood loss (11% v 3%, respectively; P = .004), and mucus loss (27% v 15%, respectively; P = .005). Satisfaction with bowel function was significantly lower and the impact of bowel dysfunction on daily activities was greater in irradiated patients compared with patients who underwent TME alone. CONCLUSION Although preoperative short-term radiotherapy for rectal cancer results in increased local control, there is more long-term bowel dysfunction in irradiated patients than in patients who undergo TME alone. Rectal cancer patients should be informed on late morbidity of both radiotherapy and TME. Future strategies should be aimed at selecting patients for radiotherapy who are at high risk for local failure.

Risk factors for anastomotic failure after total mesorectal excision of rectal cancer

Anastomotic leakage is a major complication of rectal cancer surgery. The aim of this study was to investigate risk factors associated with symptomatic anastomotic leakage after total mesorectal excision (TME).

A multivariate analysis of limiting factors for stoma reversal in patients with rectal cancer entered into the total mesorectal excision (TME) trial: a retrospective study

BACKGROUND In many patients with rectal cancer, defunctioning stomas are created to limit the consequences of anastomotic leakage. Although intended to be temporary, a substantial proportion of these stomas might never be reversed for various reasons. We aimed to describe stoma policy by use of data from the total mesorectal excision (TME) trial in patients with rectal cancer and to identify factors that limit stoma reversal. METHODS 924 Dutch patients with rectal cancer who underwent a low anterior resection were selected from the TME trial, a prospective, randomised multicentre trial studying the effects of short-term preoperative radiotherapy in 1861 patients who underwent TME. Creation of stomas and time to stoma reversal were analysed retrospectively by use of multivariate analysis. FINDINGS In 523 of 924 (57%) patients, a primary stoma (defined as a stoma created at the time of TME) was constructed after a low anterior resection. Geographical differences in the number of primary stomas constructed were reported throughout the Netherlands. 19% of stomas that were created were never reversed. Postoperative complications and secondary constructed stomas (defined as a stoma created during a second or subsequent procedure after TME) were associated with a high likelihood of a permanent stoma. However, perioperative complications were not a limiting factor for stoma closure. INTERPRETATION Postoperative complications are an important limiting factor for stoma reversal because, after occurrence of these complications, patients and surgeons might be reluctant to reverse the stoma, so a substantial proportion of these stomas are never closed. Future guidelines for stoma creation and closure should consider these factors.

Risk factors for faecal incontinence after rectal cancer treatment

Low anterior resection (LAR) may result in faecal incontinence. This study aimed to identify risk factors for long‐term faecal incontinence after total mesorectal excision (TME) with or without preoperative radiotherapy (PRT).

Impact of the Extent of Surgery and Postoperative Chemoradiotherapy on Recurrence Patterns in Gastric Cancer

PURPOSE The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy. PATIENTS AND METHODS Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns. RESULTS With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival. CONCLUSION After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.

Low Maruyama Index Surgery for Gastric Cancer: Blinded Reanalysis of the Dutch D1-D2 Trial

A quantitative estimate of residual nodal disease after gastric cancer surgery, the Maruyama index of unresected disease (MI), proved to be a strong independent predictor of survival in a large U.S. adjuvant chemoradiation study in which surgical undertreatment was frequent. Data from the Dutch D1-D2 Lymphadenectomy Trial permit an opportunity to assess the prognostic value of this variable in a cohort with lower-stage disease treated with minimum D-1 lymphadenectomy and no adjuvant chemoradiation. Blinded to survival, and excluding those cases with missing information, the MI was calculated for 648 of the original 711 patients treated with curative intent. Survival was assessed by log-rank and multivariate Cox regression analysis. All patients have been followed for a minimum of 11 years. Overall Dutch trial findings were not affected by the absence of 63 cases with incomplete data. As expected, the median MI was 26, much lower than in the previous U.S. study. In contrast to the D level, MI < 5 proved to be a strong predictor of survival by both univariate and multivariate analysis. The MI was an independent predictor of both overall survival [P = 0.016; hazard ratio (HR) = 1.45; 95% confidence interval (CI) 1.07–1.95] and relapse risk (P = 0.010; HR = 1.72; 95% CI 1.14–2.60). A strong dose-response reaction with respect to the MI and survival was also observed. We conclude that in this trial low-MI surgery is associated with enhanced survival, whereas outside of certain subgroups routine D2 lymphadenectomy is not. This observation suggests that surgeons might have more of an impact on patient survival by achieving a low-MI operation than a particular D level. A compelling dose-response effect reveals that the MI is a quantitative yardstick for assessing the adequacy of lymphadenectomy in gastric cancer.

Metastatic lymph node ratio in stage III rectal cancer; prognostic significance in addition to the 7th edition of the TNM classification

AIMS Optimal staging in rectal cancer is indispensable for the decision on further treatment and estimation of prognosis. This study assesses the prognostic capacity of the metastatic lymph node ratio (LNR) in addition to the new TNM classification. METHODS LNR was determined, in stage III patients from the Dutch TME-trial. Six year median follow up data from the trial database were used to analyse the relation of LNR to overall survival (OS) and local recurrence (LR). The relation of LNR to lymph node yield was assessed and appropriate cut off values of LNR for clinical use were determined. RESULTS 605 patients were analyzed. 278 underwent pre-operative radiotherapy. 82 patients developed a local recurrence and 289 distant metastases. LNR was an independent risk factor for OS, hazard ratio (HR) 2.10 (95% CI 1.35-3.27) (in addition to age >= 65 years, involved circumferential resection margin (CRM) and new TNM stage) and LR, HR 2.25 (95% CI 1.02-4.56) (in addition to pre-operative radiotherapy and involved CRM). LNR is predictive of OS and LR from a lymph node yield of more than one and more than five respectively. A LNR value of 0.60 offers the best cut off to identify high risk patients (5-years OS was 61 vs. 32%, HR 2.45 (95% CI 1.96-3.08) and 5-years LR rate 12.6 versus 16.3%, HR 1.65 (95% CI 1.03-2.64)). CONCLUSIONS LNR is an independent risk factor for OS and LR in addition to the 7th edition of the TNM classification. It can aid in predicting prognosis and identifying patients that should be considered for adjuvant treatment.

Nationwide outcome registrations to improve quality of care in rectal surgery. An initiative of the European Society of Surgical Oncology.

In recent years there have been significant improvements in rectal cancer treatment. New surgical techniques as well as effective neoadjuvant treatment regimens have contributed to these improvements. Key is to spread these advances towards every rectal cancer patient and to ensure that not only patients who are treated within the framework of clinical trials may benefit from these advancements. Throughout Europe there have been interesting quality programmes that have proved to facilitate the spread of up to date knowledge and skills among medical professionals resulting in improved treatment outcome. Despite these laudable efforts there is still a wide variation in treatment outcome between countries, regions and institutions, which calls for a European audit on cancer treatment outcome. J. Surg. Oncol. 2009;99:491–496.

Improved regional control and survival with “low Maruyama Index” surgery in gastric cancer: autopsy findings from the Dutch D1-D2 Trial

Based on more than 11 years of follow-up, autopsy-based analysis of recurrence in the Dutch D1-D2 Trial permits meaningful assessment of patterns of failure with respect to the Maruyama Index (MI). We previously reported that a low Maruyama Index was an independent predictor of both overall and disease-specific survival. Autopsy results are available for 441 deaths on study. Distant-only failure (15% vs 13%) was no different between the MI categories, but isolated “regional” failure (8% for MI < 5 group vs 21%) and “regional + distant” failure (19% for MI < 5 group vs 36%) occurred less frequently in the MI < 5 group (P < 0.001). We conclude that “low Maruyama Index” surgery enhances regional control and survival but does not alter the occurrence of isolated distant metastases unassociated with regional failure. Our results speak to the substantial survival value of local-regional control in this disease.