Corrie A.M. Marijnen

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.

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 ≤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 ≤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 ≤2 mm.

Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.

BACKGROUND Few prospective studies have been performed about the impact of preoperative radiotherapy (PRT) or total mesorectal excision (TME) on health-related quality of life (HRQL) and sexual functioning in patients with resectable rectal cancer. This report describes the HRQL and sexual functioning of 990 patients who underwent TME and were randomly assigned to short-term PRT (5 x 5 Gy). PATIENTS AND METHODS The Rotterdam Symptom Check List supplemented with additional items was used with questionnaires before treatment and at 3, 6, 12, 18, and 24 months after surgery. Patients without a recurrence the first 2 years were analyzed (n = 990). RESULTS Few differences were found in HRQL between patients treated with or without PRT. Daily activities were significantly less for PRT patients 3 months postoperatively. Irradiated patients recovered slower from defecation problems than TME-only patients (P = .006). PRT had a negative effect on sexual functioning in males (P = .004) and females (P < .001). Irradiated males had more ejaculation disorders (P = .002), and erectile functioning deteriorated over time (P < .001). PRT had similar effects in patients who underwent a low anterior resection (LAR) versus an abdominoperineal resection (APR). Patients with an APR scored better on the physical (P = .004) and psychologic dimension (P = .007) than LAR patients, but worse on voiding (P = .0007). CONCLUSION Short-term PRT leads to more sexual dysfunction, slower recovery of bowel function, and impaired daily activity postoperatively. However, this does not seriously affect HRQL. The comparison between LAR and APR patients demonstrates that the existence of a permanent stoma is not the only determinant of HRQL.

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.

Low Rectal Cancer: A Call for a Change of Approach in Abdominoperineal Resection

PURPOSE Despite the major improvements that have been made due to total mesorectal excision (TME), low rectal cancer still remains a challenge. METHODS By investigating a prospective randomized rectal cancer trial in which surgeons had undergone training in TME the factors responsible for the poor outcome were determined and a new method for assessing the quality of surgery was tested. RESULTS Survival differed greatly between abdominoperineal resection (APR) and anterior resection (AR; 38.5% v 57.6%, P = .008). Low rectal carcinomas have a higher frequency of circumferential margin involvement (26.5% v 12.6%, P < .001). More positive margins were present in the patients operated with APR (30.4%) compared to AR (10.7%, P = .002). Furthermore, more perforations were present in these specimens (13.7% v 2.5%, P < .001). The plane of resection lies within the sphincteric muscle, the submucosa or lumen in more than 1/3 of the APR cases, and in the remainder lay on the sphincteric muscles. CONCLUSION We systematically described and investigated the pathologic properties of low rectal cancer in general, and APR in particular, in a prospective randomized trial including surgeons who had been trained in TME. The poor prognosis of the patients with an APR is ascribed to the resection plane of the operation leading to a high frequency of margin involvement by tumor and perforation with this current surgical technique. The clinical results of this operation could be greatly improved by adopting different surgical techniques and possibly greater use of radiochemotherapy.

Gene Expression Signature to Improve Prognosis Prediction of Stage II and III Colorectal Cancer

PURPOSE This study aims to develop a robust gene expression classifier that can predict disease relapse in patients with early-stage colorectal cancer (CRC). PATIENTS AND METHODS Fresh frozen tumor tissue from 188 patients with stage I to IV CRC undergoing surgery was analyzed using Agilent 44K oligonucleotide arrays. Median follow-up time was 65.1 months, and the majority of patients (83.6%) did not receive adjuvant chemotherapy. A nearest mean classifier was developed using a cross-validation procedure to score all genes for their association with 5-year distant metastasis-free survival. RESULTS An optimal set of 18 genes was identified and used to construct a prognostic classifier (ColoPrint). The signature was validated on an independent set of 206 samples from patients with stage I, II, and III CRC. The signature classified 60% of patients as low risk and 40% as high risk. Five-year relapse-free survival rates were 87.6% (95% CI, 81.5% to 93.7%) and 67.2% (95% CI, 55.4% to 79.0%) for low- and high-risk patients, respectively, with a hazard ratio (HR) of 2.5 (95% CI, 1.33 to 4.73; P = .005). In multivariate analysis, the signature remained one of the most significant prognostic factors, with an HR of 2.69 (95% CI, 1.41 to 5.14; P = .003). In patients with stage II CRC, the signature had an HR of 3.34 (P = .017) and was superior to American Society of Clinical Oncology criteria in assessing the risk of cancer recurrence without prescreening for microsatellite instability (MSI). CONCLUSION ColoPrint significantly improves the prognostic accuracy of pathologic factors and MSI in patients with stage II and III CRC and facilitates the identification of patients with stage II disease who may be safely managed without chemotherapy.

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.

Prediction of survival in patients with metastases in the spinal column: results based on a randomized trial of radiotherapy.

Adequate prediction of survival is important in deciding on treatment for patients with symptomatic spinal metastases. The authors reviewed 342 patients with painful spinal metastases without neurologic impairment who were treated conservatively within a large, prospectively randomized radiotherapy trial. Response to radiotherapy and prognostic factors for survival were studied.