UPDATE: ENDOMETRIAL CANCER
Are lymphadenectomy and external-beam radiotherapy valuable in women who have an endometrial malignancy? Debate over the standard of care continues.
IN THIS ARTICLE
Randomization in a prospective study is supposed to equalize the risks between groups. In the ASTEC trial, despite randomization, there were 10% more patients who had deeply invasive disease in the lymphadenectomy group, along with 3% more adverse histologies and high-grade (grade-3) tumors. Given the higher incidence of positive nodes and poorer outcome in these cases, this difference may have had a significant impact on the evaluation of the groups for overall or disease-specific survival.
External-beam radiotherapy reduces local recurrence of endometrial Ca but does not improve survival
ASTEC/EN.5 Study Group, Blake P, Swart AM, Orton J, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009;373:137–146.
Radiation therapy has been a standard treatment for endometrial cancer when there is high risk of recurrence. This report combines two independent randomized, controlled trials investigating the benefit of postoperative adjuvant pelvic radiation in women who had early-stage disease and who met histologic criteria for high risk of recurrence and death. The trials are the EN.5 trial from Canada, and the radiation-therapy randomization of the ASTEC trial). Neither found a benefit in terms of overall survival, disease-specific survival, or recurrence-free survival, although local recurrence was reduced by 2.9% The authors also provide a review of the literature and a meta-analysis of other randomized, controlled trials on this subject.
Details of the EN.5 and ASTEC radiation-therapy trials
Criteria for enrollment were similar for the two trials, which focused on women who had histologically confirmed endometrial cancer and an intermediate or high risk of recurrence. This included women who had FIGO stage IA or stage IB (grade 3), stage IC (all grades), or papillary serous or clear-cell histology (all stages).
Survival is the primary goal of cancer treatment. External-beam radiotherapy does not improve survival, but does provide a small but real increase in local control. Regrettably, this improvement in local control comes at a cost: 3% of patients experience acute severe or life-threatening toxicity from treatment. The absolute difference in local recurrence between women who received external-beam radiotherapy and those who did not was only 2.9%. Local recurrences are largely salvageable in women who have not been irradiated.
Therefore, external-beam radiotherapy, as delivered in this trial, regardless of node status, should not be the standard of care. Improvement in technology with intensity-modulated radiotherapy, and the further evaluation of vaginal brachytherapy alone, may provide new ways to apply this kind of treatment in endometrial cancer.
This aspect of endometrial cancer treatment clearly needs further investigation. Trials are under way that may determine the role of radiation therapy in women who have endometrial cancer.—DAVID G. MUTCH, MD; B. J. RIMEL, MD
Lymphadenectomy was not required for patients enrolled in EN.5, but was part of the surgical randomization for ASTEC. This distinction could confound the results of the combined trials, as the investigators were trying to answer two questions within one patient population.
In both the EN.5 and ASTEC trials, women were randomized to observation or external-beam radiotherapy, with these parameters:
- Radiation therapy was to begin no later than 12 weeks after surgery (most patients began radiation therapy 6 to 8 weeks after surgery)
- For ASTEC, the target dosage was 40–46 Gy in 20–26 daily fractions to the pelvis, with treatment five times each week. For EN.5, the dosage and timing were very similar: 45 Gy, 25 daily fractions, five times weekly
- In both trials, vaginal brachytherapy was allowed if it was the local practice or the center’s policy
- Women were classified as being at intermediate risk or high risk, based on the likelihood of distant recurrence, as defined by GOG99 and PORTEC1 studies. Intermediate risk included all patients who had stage-IA or -IB (grade-3) or stage-IC or -IIA (grade-1 or -2) disease. Women who had papillary serous or clear-cell histology, stage-IC or -IIA (grade-3) disease, or any stage-IIB disease were considered at high risk.
The primary outcome evaluated for both trials was overall survival. Secondary endpoints were:
- disease-specific survival
- recurrence-free survival
- locoregional recurrence
- treatment toxicity.
A total of 905 women were enrolled in the ASTEC and EN.5 trials, with most patients having endometrial histology (83%) and being categorized as at intermediate risk (75%). Approximately half the patients in both trials received brachytherapy, which was allowed according to local practice. Only 47% of the observation group actually received no treatment.
Findings were remarkably similar in EN.5 and ASTEC
Here are the main findings:
- no difference between groups in overall survival, disease-specific survival, and recurrence-free survival
- significantly fewer isolated vaginal or pelvic initial recurrences in the external-beam radiotherapy group, with an absolute difference of 2.9%. (Only 35% of all recurrences were isolated recurrences)
- no significant difference between groups in distant or local and distant recurrences
- as expected, higher toxicity in the group receiving external-beam radiotherapy, including life-threatening toxicity (acute toxicity, 3% vs <1%; late toxicity, 1% vs 0%).
