• GOG-99 Trial—The next randomized trial, GOG-99, studied 392 patients with stage I/II endometrial carcinoma who underwent total abdominal hysterectomy–bilateral salpingo oophorectomy (TAH-BSO) with lymphadenectomy followed by postoperative pelvic radiation therapy or no further therapy. Patients had stage IB, IC, or occult IIA/B disease. Radiation therapy consisted of wholepelvic radiation therapy to a total dose of 50.4 Gy.
Estimated 2-year recurrence rates were 3% in the radiation therapy group and 12% in the group that received no additional therapy after surgery (P < .01). There were 18 pelvic or vaginal recurrences in the group that did not get adjuvant radiation therapy compared to three in the radiation therapy group, two of whom actually refused radiation therapy. Four-year survival rates (86% vs 92%) favored the radiation therapy group but this difference was not statistically significant.
An unplanned subset analysis was conducted for which patients were divided into high- and low-intermediate- risk groups based on four prognostic factors: age, high grade (grade 2 or 3), invasion of the outer one-third of the myometrium, and LVSI. High-intermediate-risk patients were at least 70 years old with one risk factor, at least 50 years old with two risk factors, or any age with all three risk factors. When examining recurrence with these risk factors taken into consideration, the relative hazard of recurrence among high-intermediaterisk patients who received radiation therapy was 0.42 (0.21–0.83) at 4 years. In other words, there was a 58% hazard reduction with the addition of radiation therapy. High-intermediaterisk patients, while making up 33% of patients, constituted 67% of all recurrences. For survival analysis, the relative hazard associated with radiation therapy was 0.86 (P > .05), but for high-intermediate-risk patients, the hazard rate was 0.73 (0.43–1.26).
• ASTEC/EN.5 Trials—The ASTEC (A Study in the Treatment of Endometrial Cancer) and EN.5 trials randomized 906 patients to adjuvant pelvic external-beam radiation therapy (40–46 Gy in 20–25 fractions) or no adjuvant external-beam radiation therapy. Vaginal brachytherapy could be used regardless of the externalbeam randomization, and the total dose was 4 Gy in two fractions via high dose-rate radiation or 15 Gy via low dose-rate in the ASTEC trial—the EN.5 did not specify the brachytherapy. Treatment centers were required to decide in advance whether they would offer brachytherapy to all patients or to no patients. Brachytherapy was given to 54% of the patients in the external-beam radiation therapy arm and 53% of patients in the observation arm. Morbidity was 57% in the external-beam radiation therapy arm compared to 27% in the arm receiving no external-beam radiation therapy (no P value available).
Only 92% of patients randomized to the external-beam radiation therapy arm actually received external-beam radiation therapy, and only 82% of patients received at least 40 Gy of external-beam radiation therapy to the whole pelvis. With a median follow-up of 58 months, the 5-year hazard ratio for overall and disease-specific survival were not significantly different between the two groups. The 5-year hazard ratio for an isolated pelvic or vaginal recurrence was 0.46 (95% confidence interval = 0.24–0.89; P = .02), favoring the group that received radiation therapy, with recurrence incidences of 6.1% and 3.2% in the observation and external-beam radiation therapy arms, respectively. This trial shows a small improvement in locoregional control but no survival benefit. Limitations to the interpretation of the trial include low radiotherapy compliance, no discussion of radiotherapy quality assurance, the nonrandomized nature of brachytherapy use, and significant heterogeneity of inclusion criteria and staging.
• Pelvic Irradiation—Adjuvant pelvic radiation therapy results in a clinically important decrease in locoregional recurrence in selected intermediate-risk endometrial cancer patients. While no improvement in survival was noted in the above trials with the addition of pelvic radiotherapy, competing morbidities in this patient population limit the power of even large studies over longer followup periods. The inclusion of low-risk patients and inadequate power may, in turn, limit the ability of these studies to detect small but important survival differences. For well-selected patients, improvement in local control may affect survival given that not all locoregional recurrences are salvaged. In addition, the substantial morbidity of salvage therapy should not be understated.
• SEER Analysis—An analysis of the Surveillance, Epidemiology and End Results (SEER) database of the National Cancer Institute was conducted to evaluate the survival outcome of 21,249 patients treated for stage I endometrial cancer between 1988 and 2001. Patients with N1 or M1 disease, as well as those without pathologic staging, were excluded. Approximately 19% of patients studied had radiation therapy. Of those who received radiation therapy, 89% had external-beam radiation therapy. On multivariate analysis with relative survival as an endpoint, use of radiation therapy showed a hazard ratio of 0.45 for IC, grade 1 patients (P < .001) and 0.74 for stage IC, grade 3/4 patients (P = .009).
• Vaginal Brachytherapy—Since a large proportion of the locoregional recurrences are in the vagina or vaginal vault, some authors have hypothesized that postoperative vaginal brachytherapy alone may prevent the majority of locoregional recurrences. Many single-institution trials have shown acceptable locoregional control rates using vaginal brachytherapy alone.[21‑29] Furthermore, since the addition of pelvic radiation therapy increases side effects, it would be beneficial to limit external-beam radiation therapy to those whose risk of recurrence is high, based on the risk factors noted above.
• PORTEC-2—The PORTEC-2 trial, available at this time only in abstract form, was designed to compare postoperative externalbeam pelvic radiation therapy to postoperative vaginal brachytherapy. A total of 427 patients with high-intermediate risk endometrial cancer were randomized. High-intermediate risk was defined as: (1) age ≥ 60 and stage IC, grade 1/2; (2) age ≥ 60 and stage IB, grade 3; or (3) any age and stage IIA, grade 1/2, or grade 3 with < 50% myometrial invasion.
With a median follow-up of 34 months, 3-year actuarial vaginal relapse rates were 0.9% in the vaginal brachytherapy arm compared with 2.0% in the external-beam pelvic radiation therapy arm (P = .97). Pelvic relapse rate was 0.7% with externalbeam radiation therapy and 3.6% with vaginal brachytherapy (P = .03). Distant recurrence rate, recurrence-free survival, and overall survival were not significantly different between the two arms. Three-year rates of vaginal, pelvic, and distant relapse as sites of first failure were 0%, 1.3%, and 6.4% in the vaginal brachytherapy group and 1.6%, 0.7%, and 6.0% in the pelvic radiation therapy group. There was no significant difference in recurrence- free or overall survival.
The incidence of gastrointestinal grade 1 toxicities was 35% in the external-beam radiation therapy arm compared with 12% in the vaginal brachytherapy group. Grade 2 toxicity rates were 19% in the whole-pelvis radiation therapy group vs 7% in the vaginal brachytherapy group (P ≤ .001). Grade 1 skin toxicity rates were 6% for the external-beam radiation therapy group and 1% for the vaginal brachytherapy group, and grade 2 toxicity rates were 3% and 0%, respectively (P ≤ .001).
The authors concluded that vaginal brachytherapy should be the treatment of choice for patients with high-intermediate risk of recurrence.
• Local Recurrence — Most of the above trials show an increased local recurrence rate without adjuvant radiation therapy in intermediate-risk patients. Five-year overall survival after local recurrence has been noted to range from 18% to 66%.[31-39] Of the 13 GOG-99 patients whose disease recurrence developed in the vagina alone, five had died from endometrial cancer by the time of publication.
A retrospective review studied 91 patients treated with radiation therapy for vaginal recurrences at M.D. Anderson Cancer Center between 1960 and 1997. Approximately 74% of patients had stage I disease; 63% of these patients had not received radiation therapy as a part of their initial treatment plan. Of 91 patients, 80 received external-beam radiation therapy for their recurrence, with 52 also receiving brachytherapy. Eleven patients received brachytherapy alone. Local control rates were 82% and 75% at 2 and 5 years, respectively, and overall survival rates were 69% and 43% for the same time points. The local recurrence was not controlled in 18 patients, and 23 patients had treatment failure distantly as their next site of recurrence.
In general, outcomes are poorer in those who have a nonvaginal pelvic recurrence. Despite the possibility of salvaging some recurrences, the treatment of recurrence carries a significant morbidity. One recent study showed an 18% rate of grade 3/4 gastrointestinal toxicity and a 50% rate of grade 3 vaginal sequelae.
The intermediate-risk group thus presents a clinical challenge. Secondary risk factors including age, LVSI, exact depth, grade, and possibly tumor size must be considered when making treatment decisions, so as to balance cure and complication rates. The benefit in locoregional control with the addition of radiation therapy must be balanced with the detriment to quality of life as a result of treatment. An additional quality-of-life concern is the morbidity associated with tumor recurrence and its treatment.