Text Box: The impact of radiotherapy on survival of patients with stage I endometrial cancer Text Box: PM Tebeu (1,3), Y Popowski (2), H M Verkooijen (3), C Bouchardy (3), F Ludicke (4), M Usel (3), J M Lutz (3),  A L Major (1,4) 1) Department of Gynecology, Geneva University Hospital, 2) Division of Radio-Oncology, Geneva University Hospitals, 3) Geneva Cancer Registry, Institute for Social and Preventive Medicine, University of Geneva,  4) Fondations pour Recherches Médicale, University of Geneva
 
                         
                           
                           
                           
                           
                           
                           
                           
                           
                           
Text Box: Background and objective: Early studies showed that radiotherapy might reduce the risk of local recurrence among patients with early stage endometrial cancer (1) . Then, many physicians started to treat these patients with either brachytherapy or external radiotherapy. External radiotherapy is associated with several adverse effects, such as cystitis, bowel movements, abdominal cramps, and diarrhoea. Moreover, in case of relapse patients who received external radiotherapy have little chance to cure (5-year survival: 43% versus 65% ) (2).In addition, some studies have shown nonsignificant trends towards poorer survival in stage-I endometrial cancer patients treated with external radiotherapy.The indication and utility of radiotherapy in early stage endometrial cancer is still a subject of debate. The aim of the present study is to evaluate the impact of external radiotherapy and / or brachytherapy on the survival of patients with favourable or unfavourable stage-I endometrial tumours.  
 
                         
                           
                           
                           
                           
                           
                           
Text Box: Patients and methods: We considered all patients operated for endometrial cancer confined to the uterus (stage-I) recorded between 1980-1996 at the Geneva cancer registry. We excluded patients with stage-Ia cancer. We compared patients treated with brachytherapy only and patients treated with external radiotherapy with or without brachytherapy, to patients that received no radiotherapy. Disease specific survival was analysed by actuarial method, and compared by log-rank test. We used Cox proportional hazard analysis to calculate the risk to die of endometrial cancer according to type of radiotherapy, accounting for other prognostic factors.
 
                         
                           
                           
                           
                           
                           
Text Box: Results Table 1 describes the demographic, tumour and treatment characteristics of the 297 patients included in this study. Overall, 92 (31%) women had no radiotherapy, 94 (32%) women had brachytherapy, and 111 (37%) had external radiotherapy with or without brachytherapy. Compared to patients who received no radiotherapy, patients treated with brachytherapy were more frequently treated at the beginning of the study period and in public hospitals. Patients treated with external radiotherapy were also more often treated in the public hospitals than patients receiving no radiotherapy. In addition, they more frequently had deep myometrial invasion and their tumours were more often poorly differentiated. Accordingly, their tumour profile was more often unfavourable (stage-Ib, grade 3 or stage-Ic). We found an increased risk of death from  endometrial cancer in the overall population study (Table 2, Table 3-Panel A) For the 162 patients with favourable prognosis disease, specific survival was comparable for non-irradiated patients and patients treated with brachytherapy only (96.6% and 97.2% resp.), but lower (88.5%) for those treated with external radiotherapy. After adjusting for age, external radiotherapy significantly increased the risk to die of endometrial cancer (Hazard ratio: 11.0, 95% CI 1.4-85.0)(Table 2, Table 3-Panel B). For the 135 patients with unfavourable prognosis, the survival of non-irradiated patients (88.3%) was similar to that of patients treated with brachytherapy only (84.2%) or external radiotherapy (84.2%)(Table 2, Table 3 -Panel C). Among the twenty patients with stage-IC, grade 3, none of the four patients treated with surgery alone died of endometrial cancer. Among the 16 treated with external radiotherapy, 5-year disease-specific survival was 62.5%. Text Box: Table 3 Risk of death from endometrial cancer according to type of adjuvant therapy Text Box:   Text Box:   Text Box:   Text Box: Discussion Our study shows not only a lack of benefit of external radiotherapy in stage-l patients, but also an increased risk of death from endometrial cancer among women with stage IbGrade1-2. Only two randomised controlled trials have addressed the effect of radiotherapy for stage-I endometrial cancer(2,3). Aalders et al. treated all stage-I patients with brachytherapy, and randomised patients to examine the effect of external radiotherapy. They found no 5-year overall survival difference between patients in the two groups, with an unsignificant increase of death in the irradited group (89% versus 91%). Only patients with stage stage-Ic, grade 3 showed an improved survival when treated with additional external radiotherapy (73% versus 82%). A definite conclusion could not be drawn, since no statistical tests were performed between the different treatment groups, which were not adjusted for age(3). Creutzberg et al. included stage-I endometrial cancer patients with either stage-Ib, grade 2-3 or stage-Ic, grade 1-2. They randomised patients to either external radiotherapy or no adjuvant radiotherapy. After eight years of follow-up,there was also an (insignificant) excess of overall deaths in the irradiated group (29ˇ3% versus 23ˇ1% or 84 versus 68 women)(2). In conclusion, according to the current and previous studies, it is no longer justified to use external radiotherapy on patients with stage IbG1-2 and patients with IcG1-2. Additional research is needed to determine the usefulness of external radiotherapy among patients with IcG3 endometrial cancer.  We therefore conclude that the guidelines concerning external radiotherapy in stage-I endometrial cancer need urgent reassessment. Text Box: For contact: pmtebeu@yahoo.fr Text Box: References 1.Graham J. The value of preoperative or postoperative treatment by radium for carcinoma of the uterine body. Surg Gynecol Obstet 1971; 132(5):855-60. 2. Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, De Winter KA, Lutgens LC, van den Bergh AC, Steen-Banasik E, Beerman H, van Lent M. Survival after relapse in patients with endometrial cancer: results from a randomized trial. Gynecol Oncol 2003; 89(2):201-9. 3. Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980;56(4):419-27.                                                                                                                                    Contact: pmtebeu@yahoo.fr Text Box: GRELL,  Montpellier,France  2004 Text Box: