December 16, 2008 — In women with early endometrial cancer, pelvic lymphadenectomy or external-beam radiotherapy provide no survival benefit and should not be used routinely, according to 2 studies reported in the December 13 Online First issue of The Lancet. One study showed no benefit of pelvic lymphadenectomy in overall or recurrence-free survival for women with early endometrial cancer, and the second study showed that 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.
"Hysterectomy and bilateral salpingo-oophorectomy (BSO) is the standard surgery for stage I endometrial cancer," write H. Kitchener, from the University of Manchester, School of Cancer and Imaging Sciences in Manchester, United Kingdom, and colleagues from the writing committee of the Medical Research Council A Study in the Treatment of Endometrial Cancer (MRC ASTEC) study group. "Systematic pelvic lymphadenectomy has been used to establish whether there is extra-uterine disease and as a therapeutic procedure; however, randomised trials need to be done to assess therapeutic efficacy. The ASTEC surgical trial investigated whether pelvic lymphadenectomy could improve survival of women with endometrial cancer."
This trial, which took place at 85 centers in 4 countries, enrolled 1408 women with histologically proven endometrial carcinoma thought before surgery to be confined to the uterine corpus. With use of a minimization method, participants were randomly assigned 1:1 to undergo standard surgery (hysterectomy and BSO, peritoneal washings, and palpation of para-aortic nodes) or standard surgery plus pelvic lymphadenectomy (n = 704).
Overall survival was the main study endpoint, and analysis was by intent-to-treat. Median follow-up was 37 months (interquartile range, 24 - 58 months).
Women who had early-stage disease at intermediate or high risk for recurrence were randomly assigned, independent of lymph-node status, into the ASTEC radiotherapy trial, to control for postsurgical treatment.
Of 191 deaths at follow-up, 88 were in the standard surgery group and 103 in the lymphadenectomy group. Hazard ratio (HR) was 1.16 (95% confidence interval [CI], 0.87 - 1.54; P = .31) favoring standard surgery. Absolute difference in 5-year overall survival was 1% (95% CI, –4 to 6).
Of 251 women who died or had recurrent disease, 107 were in the standard surgery group and 144 in the lymphadenectomy group, yielding an HR of 1.35 favoring standard surgery (95% CI, 1.06 - 1.73; P =.017). Absolute difference in 5-year recurrence-free survival was 6% (95% CI, 1 - 12).
HR was 1.04 for overall survival (95% CI, 0.74 - 1.45; P = .83) and 1.25 for recurrence-free survival (95% CI, 0.93 - 1.66; P = .14), after adjustment for baseline characteristics and pathologic details.
"Our results show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women with early endometrial cancer," the study authors write. "Pelvic lymphadenectomy cannot be recommended as routine procedure for therapeutic purposes outside of clinical trials."
Limitations of this study were that the lymphadenectomy specified in the protocol was not comprehensive and did not include all pelvic and para-aortic nodes, and there was a possible failure to report mild lymphoedema (moderate and severe lymphoedema were worse in the lymphadenectomy group).
"The balance of risks and benefits for systematic lymphadenectomy does not favour this intervention, with no clear evidence of benefit in terms of overall or recurrence-free survival and increased risk of lymphoedema," the study authors conclude. "Although the results do not invalidate the use of lymphadenectomy for surgical staging to identify the need for adjuvant treatment, our results suggest that lymphadenectomy in itself has no therapeutic effect and is therefore not justified as a therapeutic procedure in its own right."
The second report was a systematic review and meta-analysis of pooled trial results from the ASTEC and EN.5 studies regarding adjuvant external-beam radiotherapy in the treatment of endometrial cancer.
"External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence," write P. Blake, from Royal Marsden Hospital in London, United Kingdom, and colleagues. "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."
ASTEC (n = 789) and EN.5 (n = 116) enrolled 905 women with intermediate-risk or high-risk early-stage disease from 112 centers in the United Kingdom, Canada, Poland, Norway, New Zealand, Australia, and the United States. Between July 1996 and March 2005, participants were randomly assigned after surgery to observation (n = 453) or to external-beam radiotherapy (n = 452). The radiotherapy protocol specified a target dose of 40 to 46 Gy in 20 to 25 daily fractions to the pelvis, with treatment 5 times per week. Overall survival was the primary outcome measure, and all analyses were by intent-to-treat. Median follow-up was 58 months.
Of 135 deaths at follow-up, 68 were from the observation group and 67 were from the external-beam radiotherapy group. Overall survival was no better with external-beam radiotherapy vs observation (HR, 1.05; 95% CI, 0.75 - 1.48; P = .77). In both groups, 5-year overall survival was 84%. A meta-analysis of trials combining data from ASTEC and EN.5 confirmed that there was no benefit of external radiotherapy on overall survival (HR, 1.04; 95% CI, 0.84 - 1.29). In addition, the meta-analysis ruled out an absolute benefit of external-beam radiotherapy at 5 years of more than 3%.
At 5 years, the local recurrence rate in the observation group was 6.1%. It should be noted that in ASTEC and EN.5, brachytherapy was used in 53% of women.
"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 study authors write. "The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity....Brachytherapy is a more convenient treatment than external beam radiotherapy and might be associated with less toxicity."
Limitations of the study include lack of central pathology review of specimens in ASTEC, and inability to draw firm conclusions about any possible interaction of lymphadenectomy and postoperative adjuvant external radiotherapy.
In an accompanying editorial, Michael Höckel and Nadja Dornhöfer, from the University of Leipzig in Leipzig, Germany, note that "less may be more" for most patients with early-stage endometrial cancer, and that "different may be better" for patients with high-risk tumors.
"Appropriate studies need to explore whether locoregional tumour control can be improved and distant metastases prevented by better surgery and different systemic therapies," Drs. Höckel and Dornhöfer write. "These could include first, for all cases, modified THBSO [total hysterectomy and bilateral salpingo-oophorectomy], including resection of the vaginal cuff with techniques that minimise tumour dissemination and endopelvic secondary healing. Second, for the preoperatively and intraoperatively identified high-risk cases, modified pelvic lymph-node dissection on the basis of embryologically defined pelvic visceroparietal compartmentalisation and complete inframesenteric and supramesenteric periaortic lymph-node dissection with resection of the infundibulopelvic ligaments."
"Third, for the postoperatively established high-risk cases, adjuvant chemotherapy. Paclitaxel-carboplatin seems to be an appropriate candidate combination," Drs. Höckel and Dornhöfer conclude. "Another important avenue of research should be the identification of high-risk cases in early-stage disease by molecular markers or gene signatures."
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