J.W.H. Leer

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.

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.

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.

Local Recurrence After Breast-Conserving Therapy for Invasive Breast Cancer: High Incidence in Young Patients and Association with Poor Survival

PURPOSE To study risk factors for local recurrence (LR) after breast-conserving therapy (BCT) for invasive breast cancer and, for patients with an LR, the mode of detection, location, treatment, influence of radiation therapy, and impact on survival. METHODS AND MATERIALS 1360 patients (median age 52 years; range 24-88) with a total of 1393 pT1-2 N0-1 tumors treated with BCT between 1980-1994 were studied (median follow-up 52 months). The adequacy of radiation treatment of the patients developing LR was studied in a quality control study. The impact of LR on overall survival and distant metastasis was studied in a Cox regression model with LR as a time-dependent covariate. RESULTS A total of 88 LR occurred with a 5- and 10-year LR risk of 8 and 12%. Age was the only significant risk factor. Compared to patients > 65 years old, patients < 45 years old and patients 45-65 years old had a relative risk (RR) of 4.09 and 2.41, respectively, of developing LR. Risk on LR was found to increase gradually with younger age. Radiation therapy was considered adequate and did not play a role in influencing the LR rate. Almost 65% of the LR were true or marginal recurrences. Of all LR, 80% appeared during the first 5 years and were detected with equal frequency by the patient herself, the physician, and annual mammography. LR was a major predictor for distant metastasis (RR: 4.90; 3.15-7.62) and death (RR: 4.29; 2.93-6.28). CONCLUSION Young age is a major risk factor for LR and there is a significant gradual increase in LR with decreasing age. LR is associated with a higher risk of distant metastasis and death. Whether LR is the cause of or a marker for distant metastasis remains unresolved.

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.

Utility assessment in cancer patients : adjustment of time tradeoff scores for the utility of life years and comparison with standard gamble scores

The standard gamble (SG) and the time tradeoff (TTO), two frequently used methods of utility assessment, have often been found to lead to different utilities for the same health state. The authors investigated whether adjustment of TTO scores for the utility of life years (risk attitude) eliminated this difference. In addition, the association between risk attitude and sociodemographic and medical variables was studied. In 30 disease-free testicular cancer patients, SG and TTO were used to assess the utilities of four health profiles relevant to testicular cancer. Utility of life years was estimated from certainty equivalents (CEs). SG scores were significantly higher than unadjusted TTO scores for all profiles. As the majority of patients (85%) were risk-averse, CE-adjusted TTO scores were higher than unadjusted scores, and were not significantly different from those obtained from the SG for three of the four profiles. However, adjusted scores were still slightly but consistently lower than SG scores. Possible explanations for this discrepancy are discussed. An association was found between risk aversion and medical treatment: patients who had received chemotherapy for their cancers were more risk-averse than were patients who had been in a surveillance protocol only. As risk aversion can have an impact on treatment decisions, it is important to assess the risk posture of the patient to whom the decision pertains. Key words: utility assessment; QALY; risk aversion; oncology; treatment preferences. (Med Decis Making 1994;14:82-90)

The volume effect in radiation-related late small bowel complications: results of a clinical study of the EORTC Radiotherapy Cooperative Group in patients treated for rectal carcinoma

PURPOSE The purpose of this study was to quantify the correlation between irradiated small bowel volume and late occurring small bowel complications. METHODS Small bowel volumes in the high-dose region were measured using orthogonal barium films for 203 patients treated for rectal carcinoma with pelvic postoperative radiotherapy to 50 Gy in an EORTC multicentric study. RESULTS The 5-year estimate of late pelvic small bowel obstruction requiring surgery was 11%. No correlation between the irradiated small bowel volume and obstruction was detected. The actuarial 5-year estimate of chronic diarrhea varied from 31% in patients with irradiated small bowel volumes below 77 cm3 to 42% in patients with volumes over 328 cm3. This correlation was significant in the univariate and multivariate analysis (p = 0.025). The type of rectal surgery significantly influenced the incidence of chronic diarrhea and malabsorption, the actuarial 5-year estimate being 49% and 26% after low anterior resection and abdominoperineal resection, respectively (p = 0.04). CONCLUSIONS This study demonstrated that there is a volume-effect in radiation-induced diarrhea at a dose of 50 Gy in 25 fractions. No volume-effect for small bowel obstruction was detected at this dose-level in pelvic postoperative radiotherapy. A review of the literature data on small bowel obstruction indicates that the volume effect at this dose level can only be demonstrated in patients who were treated with extended field radiotherapy (estimated small bowel volume 800 cm3) after intra-abdominal surgery.

Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prostpective randomsied trial with standard operative and histopathological techniques. Dutch Colorectal Cancer Group.

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.

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.