It was anticipated that there would be difficulty drawing conclusions due to the limited number of studies, variety of comparisons, small numbers, reporting of analyses, lack of pathology review, and lack of power in subgroup analyses. With the limited data, it is important to highlight the weaknesses of the data, as well as the commonalities, to help inform treating physicians and patients about the role of adjuvant radiotherapy for patients with early-stage endometrial cancer. Only five randomized trials were available for review. Two trials compared similar adjuvant treatment (external bean radiotherapy [EBRT] vs. no further treatment), with one of the trials including patients who were completely surgically staged and the other trial including patients who were non-surgically staged. All of the trials included a proportion of patients at a low risk of recurrence, a population not generally considered for adjuvant radiotherapy. One trial, upon pathology review, reported that a substantial number of patients were shifted from grade 2 to grade 1, and, as such, 134 patients would not have met the eligibility requirements for participation in that trial. None of the trials was designed to detect statistically significant differences in survival or in subgroup populations.
Despite the noted limitations of the available evidence, patients and clinicians are still faced with treatment decisions regarding adjuvant therapies for early-stage endometrial cancer. In three randomized trials, regardless of surgical staging, the addition of EBRT significantly improved pelvic control, but not survival, when compared with no further treatment or to intracavitary radiotherapy (ICRT) alone. While not statistically comparable, the trials were also consistent in reporting differences in pelvic recurrences among women at intermediate to high risk of recurrence in favour of the radiotherapy group over the control group. In those trials, EBRT was also associated with significant mild adverse effects, as well as a low incidence of significant acute and late adverse effects.
Ultimate pelvic control following salvage radiotherapy was reported in only one of the randomized trials. The benefit of that strategy is that if the ultimate pelvic control rates were found to be definitively equivalent, radiotherapy could be reserved to treat documented recurrences, and fewer women would be exposed to radiotherapy and its adverse effects. Patients may, however, derive a psychological benefit from adjuvant radiotherapy, especially given the significant improvements in pelvic control. While the Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) study reported pelvic control and survival after relapse, ultimate pelvic control rates according to treatment arm by risk-subgroup based on an intention to treat analyses are not readily available.
The role of surgical staging is controversial. The advantage of surgical staging is that it selects out patients who may not need adjuvant pelvic radiotherapy. It is possible that patients with high-grade disease might be spared adjuvant treatment in the absence of metastatic nodal disease after surgical staging - they would likely have received adjuvant treatment had they not undergone surgical staging. The disadvantage of surgical staging is that there are potential risks, such as injury to nerves or blood vessels and the development of lymphocysts. Furthermore, that procedure requires the expertise of a gynecologic oncologist. Patients may have to wait or travel long distances to a tertiary care centre in order to have that procedure. Finally, there is only one prospective randomized trial that has compared surgical staging to non-surgical staging (i.e., hysterectomy with bilateral salpingo-oophorectomy, no lymphadenectomy). It does not appear that surgical staging confers a survival benefit in early endometrial cancer. Therefore, the decision to offer surgical staging may require consultation with a gynecologic oncologist, and the decision may subsequently have an impact on the decision to offer adjuvant radiotherapy.
The limited information available from the five randomized trials and four systematic reviews highlights the need to conduct well-designed randomized controlled trials evaluating different interventions. Results from such studies would be extremely helpful in clarifying the role of those interventions in patients with stage I endometrial cancer. Unfortunately, no randomized trial has been published comparing adjuvant EBRT to adjuvant ICRT, although a study examining this is currently being conducted (PORTEC2). In the absence of evidence directly comparing EBRT to ICRT, it is not possible to comment on relative efficacy and toxicities of those approaches.
