E. Klein Kranenbarg

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).

Acute Side Effects and Complications After Short-Term Preoperative Radiotherapy Combined With Total Mesorectal Excision in Primary Rectal Cancer: Report of a Multicenter Randomized Trial

PURPOSE Total mesorectal excision (TME) surgery in the treatment of rectal cancer has been shown to result in a reduction in the number of local recurrences in retrospective studies. Reports on improved local control after preoperative, hypofractionated radiotherapy (RT) have led to the introduction of a prospective randomized multicenter trial, in which the effect of TME surgery with or without preoperative RT were evaluated. Any benefit in regard to a reduced local recurrence rate and possible improved survival must be weighed against potential adverse effects in both the short-term and the long-term. The present study was undertaken to assess the acute side effects of short-term, preoperative RT in rectal cancer patients and to study the influence of five doses of 5 Gy on surgical parameters, postoperative morbidity and mortality in patients randomized in the Dutch TME trial. PATIENTS AND METHODS We analyzed 1,530 Dutch patients entered onto a prospective randomized trial, comparing preoperative RT with five doses of 5 Gy followed by TME surgery with TME surgery alone, of which 1,414 patients were assessable. Toxicity from RT, surgery characteristics, and postoperative complications and mortality were compared. RESULTS Toxicity during RT hardly occurred. Irradiated patients had 100 mL more blood loss during the operation (P <.001) and showed more perineal complications (P =.008) in cases of abdominoperineal resection. The total number of complications was slightly increased in the irradiated group (P =.008). No difference was observed in postoperative mortality (4.0% v 3.3%) or in the number of reinterventions. CONCLUSION Preoperative hypofractionated RT is a safe procedure in patients treated with TME surgery, despite a slight increase in complications when compared with TME surgery only.

Radiotherapy does not compensate for positive resection margins in rectal cancer patients: report of a multicenter randomized trial

PURPOSE Circumferential resection margin (CRM) involvement is a prognostic factor for local recurrence in rectal cancer. In a randomized trial comparing preoperative radiotherapy (5 x 5 Gy), followed by total mesorectal excision (TME) with TME alone, we demonstrated the beneficial effect of short-term preoperative radiotherapy on local recurrences. Here we evaluate the effect of radiotherapy on local recurrence rates in patients with different CRM involvements. METHODS AND MATERIALS Circumferential margins were defined as positive (< or =1 mm), narrow (1.1-2 mm), or wide (>2 mm). Postoperative radiotherapy was mandatory for surgery-only patients with a positive CRM, but was not always administered and enabled us to compare local recurrence rates for patients with or without postoperative radiotherapy. Furthermore, the effect of preoperative radiotherapy was assessed in the different margin groups. RESULTS Of 120 patients in the surgery-only group with a positive CRM, 47% received postoperative radiotherapy. There was no difference in the local recurrence rate between the irradiated and nonirradiated patients (17.3% vs. 15.7%, p = 0.98). Preoperative radiotherapy was effective in patients with a narrow CRM (0% vs. 14.9%, p = 0.02) or wide CRM (0.9 vs. 5.8%, p < 0.0001), but not in patients with positive margins (9.3% vs. 16.4%, p = 0.08). CONCLUSION Preoperative hypofractionated radiotherapy has a beneficial effect in patients with wide or narrow resection margins, but cannot compensate for microscopically irradical resections resulting in positive margins.

Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer: Prospective randomised trial with standard operative and histopathological techniques

OBJECTIVE To document local recurrence in primary rectal cancer when standardised techniques of surgery, radiotherapy, and pathology are used, and to investigate whether the local recurrence rate after total mesorectal excision permits the omission of adjuvant short term preoperative radiotherapy. DESIGN Prospective randomised study. SETTING Dutch (n = 80), English (n = 1), German (n = 1), Swedish (n = 9), and Swiss (n = 1) hospitals. SUBJECTS The first 500 randomised Dutch patients with primary rectal cancer. MAIN OUTCOME MEASURES Local recurrence, survival, operation-related factors, specific pathological tumour characteristics, short and long term morbidity, and quality of life. RESULTS Between January 1996 and April 1998, 871 Dutch and 94 other patients were randomised. Our feasibility analysis shows that cooperation between and within the participating disciplines goes well. With regard to the surgical part, this can be confirmed by the large number of operations attended by consultant surgeons (58%). The number of abdominoperineal resections appeared to be low (30%), as did the percentage of lateral margins involved (13%). The rate of adverse effects of radiotherapy was acceptable. Apart from a larger operative blood loss and a higher infective complication rate in the irradiated group, no significant differences were found with regard to morbidity and mortality between the randomised groups. CONCLUSIONS The accrual of our trial is going well and it is feasible; short term preoperative radiotherapy is safe even in combination with TME.

Mechanisms of oncogenesis in colon versus rectal cancer.

Observations support the theory that development of left‐ and right‐sided colorectal cancers may involve different mechanisms. This study investigated different genes involved in oncogenesis of colon and rectal cancers and analysed their prognostic value. The study group comprised 35 colon and 42 rectal cancers. Rectal cancer patients had been treated with standardized surgery performed by an experienced rectal cancer surgeon. Mutation analysis was performed for p53 in eight colon cancers and for APC and p53 in 22 rectal cancers. MLH1, MSH2, Bcl‐2, p53, E‐cadherin and β‐catenin were investigated by immunohistochemistry in all colorectal tumours. APC mutation analysis of the MCR showed truncating mutations in 18 of 22 rectal tumours (82%), but the presence of an APC mutation was not related to nuclear β‐catenin expression (p=0.75). Rectal cancers showed significantly more nuclear β‐catenin than colon cancers (65% versus 40%, p=0.04). p53 mutation analysis corresponded well with p53 immunohistochemistry (p<0.001). Rectal cancers showed significantly more immunohistochemical expression of p53 than colon cancers (64% versus 29%, p=0.003). In rectal cancers, a significant correlation was found between positive p53 expression and worse disease‐free survival (p=0.008), but not in colon cancers. Cox regression showed that p53‐expression (p=0.03) was an independent predictor for disease‐free survival in rectal cancers. This study concluded that rectal cancer may involve more nuclear β‐catenin in the APC/β‐catenin pathway than colon cancer and/or nuclear β‐catenin may have another role in rectal cancer independently of APC. The p53‐pathway seems to be more important in rectal cancer, in which it also has independent prognostic value. When prognostic markers are investigated in larger series, differences in biological behaviour between colon and rectal cancer should be considered. Copyright

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).

Urinary dysfunction after rectal cancer treatment is mainly caused by surgery

Urinary dysfunction (UD) is common after rectal cancer treatment, but the contribution of each treatment component (surgery and radiotherapy) to its development remains unclear. This study aimed to evaluate UD during 5 years after total mesorectal excision (TME) and to investigate the influence of preoperative radiotherapy (PRT) and surgical factors.

Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer

OBJECTIVE To document local recurrence in primary rectal cancer when standardised techniques of surgery, radiotherapy, and pathology are used, and to investigate whether the local recurrence rate after total mesorectal excision permits the omission of adjuvant short term preoperative radiotherapy. DESIGN Prospective randomised study. SETTING Dutch (n = 80), English (n = 1), German (n = 1), Swedish (n = 9), and Swiss (n = 1) hospitals. SUBJECTS The first 500 randomised Dutch patients with primary rectal cancer. MAIN OUTCOME MEASURES Local recurrence, survival, operation-related factors, specific pathological tumour characteristics, short and long term morbidity, and quality of life. RESULTS Between January 1996 and April 1998, 871 Dutch and 94 other patients were randomised. Our feasibility analysis shows that cooperation between and within the participating disciplines goes well. With regard to the surgical part, this can be confirmed by the large number of operations attended by consultant surgeons (58%). The number of abdominoperineal resections appeared to be low (30%), as did the percentage of lateral margins involved (13%). The rate of adverse effects of radiotherapy was acceptable. Apart from a larger operative blood loss and a higher infective complication rate in the irradiated group, no significant differences were found with regard to morbidity and mortality between the randomised groups. CONCLUSIONS The accrual of our trial is going well and it is feasible; short term preoperative radiotherapy is safe even in combination with TME.

Operative treatment of acute complications of diverticular disease : Primary or secondary anastomosis after sigmoid resection

OBJECTIVE To assess the comparative effects of two surgical regimens on the outcome of acute complicated diverticular disease. DESIGN Retrospective study. SETTING Teaching hospital, The Netherlands. SUBJECTS 60 patients who presented with acute complicated diverticular disease. INTERVENTIONS 28 patient were treated by sigmoid resection and a Hartmann operation, and 32 by resection with primary anastomosis and defunctioning stoma. MAIN OUTCOME MEASURES Morbidity and mortality. RESULTS The severity of peritonitis and the amount of faecal contamination were similar in the 2 groups. 12 patients died (7 in the Hartmann group and 5 in the primary anastomosis group). There were 3 radiological leaks with no clinical implications in the primary anastomosis group. 6 patients in the Hartmann group and 5 in the primary anastomosis group required reoperations for intra-abdominal abscess or infection. 7 and 3 patients, respectively, developed dysfunction of their stomas, and 9/21 and 3/27, respectively, required a permanent stoma (p = 0.02, 95% confidence interval of difference 0.07 to 0.56). 3 patients in the Hartmann group developed anastomotic leaks after closure of their stomas, 1 of whom required reoperation but died. No patient developed an anastomotic leak after closure of the stoma in the primary anastomosis group. CONCLUSION Both regimens are accepted treatments for patients with acute complicated diverticular disease, but because of the higher morbidity after the Hartmann procedure we prefer primary anastomosis with covering stoma.