BACKGROUND: Early endometrial cancer with low-risk pathological features can be successfully treated by surgery alone. External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence. In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer. METHODS: Between July, 1996, and March, 2005, 905 (789 ASTEC, 116 EN.5) women with intermediate-risk or high-risk early-stage disease from 112 centres in seven countries (UK, Canada, Poland, Norway, New Zealand, Australia, USA) were randomly assigned after surgery to observation (453) or to external beam radiotherapy (452). A target dose of 40-46 Gy in 20-25 daily fractions to the pelvis, treating five times a week, was specified. Primary outcome measure was overall survival, and all analyses were by intention to treat. These trials were registered ISRCTN 16571884 (ASTEC) and NCT 00002807 (EN.5). FINDINGS: After a median follow-up of 58 months, 135 women (68 observation, 67 external beam radiotherapy) had died. There was no evidence that overall survival with external beam radiotherapy was better than observation, hazard ratio 1.05 (95% CI 0.75-1.48; p=0.77). 5-year overall survival was 84% in both groups. Combining data from ASTEC and EN.5 in a meta-analysis of trials confirmed that there was no benefit in terms of overall survival (hazard ratio 1.04; 95% CI 0.84-1.29) and can reliably exclude an absolute benefit of external beam radiotherapy at 5 years of more than 3%. With brachytherapy used in 53% of women in ASTEC/EN.5, the local recurrence rate in the observation group at 5 years was 6.1%. INTERPRETATION: Adjuvant external beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival. The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity.
Comment In: Lancet. 2009 Jan 10;373(9658):97-919070890
OBJECTIVE: To evaluate the efficacy of high dose rate vaginal brachytherapy in the treatment of International Federation of Gynecology and Obstetrics stage IB, IC, and II endometrial carcinoma after surgical staging and complete lymphadenectomy. METHODS: All patients with stage IB, IC, or II adenocarcinoma or adenosquamous carcinoma of the endometrium who received postoperative high dose rate vaginal brachytherapy at our institution between June 1, 1989, and June 1, 1999, were eligible. High dose rate vaginal brachytherapy was delivered in three fractions of 700 cGy. Retrospective chart review was performed. Kaplan-Meier estimates were calculated for disease-free and overall survival. RESULTS: One hundred sixty-four women were identified. Fifty-six percent had stage IB disease, 30% had stage IC disease, and 14% had stage II disease. Approximately one third of patients had high-grade lesions and nearly 40% had deep myometrial invasion. Median follow-up was 65 months (range 6-142 months). To date, 14 patients have had recurrence; 2 at the vaginal apex, 9 at distant sites, 1 at the pelvic sidewall, 1 simultaneously in the pelvis and at a distant site, and 1 at an unknown site. Both patients with vaginal apex recurrences had salvage therapy and are now free of disease. The overall 5-year survival and disease-free survival rates were 87% and 90%, respectively. There were no Radiation Therapy Oncology Group grade 3 or 4 toxicities. High dose rate vaginal brachytherapy was approximately $1,000 less expensive than external-beam whole-pelvic radiation. CONCLUSIONS: Adjuvant high dose rate vaginal brachytherapy in thoroughly staged patients with intermediate-risk endometrial carcinoma provides excellent overall and disease-free survival with less toxicity and at less cost compared with whole-pelvic radiation.
The study is based on data on 306 patients with endometrial cancer treated as combined (remote + contact) and only the contact exposure with low, medium and high dose rate. For comparative radiobiological evaluation of reactions of irradiated tissues there were used the following radiobiological models: factor time-dose-fractionation, the cumulative radiation effect, linear- quadratic model in the variant of biologically effective dose. Survival of endometrial cancer patients undergone combined or only the contact radiation treatment was determined by the stage of disease. In particular, the survival of patients with Stage IB endometrial cancer (combined radiation treatment) was significantly higher than in Stage IC, while in Stage IB (contact radiation treatment) was significantly higher than in Stages IC and IIB. Long-term results of radiation treatment of patients with all Stages of endometrial cancer were significantly better by 16% when only the contact radiation treatment was performed. The most preferred component of radiotherapy in women suffering from endometrial cancer with severe comorbidities was brachytherapy with high dose rate both in the combined and only contact irradiation.
The aim of the present investigation was to see if alternative histopathological parameters could identify a smaller high risk group than commonly seen using routine histopathological parameters. The material consisted of 150 primary resected patients of FIGO Ia-Ic diagnosed as endometrial carcinoma and 12 cases of atypical hyperplasias which were suspected to contain small areas of carcinoma. The patients were treated from December 1979 to April 1993 at the Department of Obstetrics and Gynecology, University Hospital, Lund, Sweden. Those with deep myometrial invasion (> 50%) were given external radiotherapy (20-30 Gy) postoperatively. The follow-up period ranged from 2.5 to 5 years with 116 patients followed-up for more than 5 years. As no therapy was given before surgery we could investigate histopathologic variables such as degree of differentiation and cytology, number of mitoses per high power field (x 40), nuclear polymorphism, mode of invasion, the extension of myometrial invasion, vessel invasion as well as grade of lymphocyte reaction around the tumour cells. We found the degree of differentiation, vessel invasion, number of mitoses, mode of invasion and cytologic abberation to be significant prognostic parameters. The frequency of deep myometrial invasion (> 50%) was extremly high (51/150 = 33%). However, this usually strong parameter was only significant when comparing stage Ia with Ic. Thus the prognostic capacity of myometrial invasion is diminished in primary hysterectomized patients. In the regression analyses only vascular invasion remained significant. By combining vascular invasion with the degree of differentiation we diminished the high-risk group consisting of candidates for further investigation and treatment. Thus a high risk group consisting of poorly differentiated carcinomas with vascular invasion was constructed comprising 24 of 139 patients with a mortality rate of 60%.
To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity.
Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity.
Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone.
Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.