Carcinoma of the endometrium is the most common gynecologic malignancy affecting women in the Western world. More than 90% of tumors are Stage I, and >80% are cured by total abdominal hysterectomy and bilateral salpingo-oophorectomy alone. However, in 10–15% of patients, the tumor recurs; about 50% of recurrences are confined to the pelvis, and about 50% of pelvic recurrences are confined to the vagina.

Postoperative pelvic radiotherapy (RT) reduces the risk of pelvic recurrence in patients whose tumors have features associated with an intermediate or a high risk of locoregional recurrence; however, the effect of RT on overall survival (OS) is uncertain. Three randomized trials have evaluated the benefit of adjuvant pelvic irradiation in patients with intermediate-risk features. All three demonstrated significant reductions in the rates of pelvic recurrence with adjuvant RT but failed to show significant improvements in OS. The authors of these studies suggested that the reason adjuvant RT had no effect on OS was that successful salvage treatment of vaginal recurrences prevented many patients with local recurrence from dying of their disease. However, the power of these studies to reveal clinically relevant effects of adjuvant pelvic RT may have been limited by the inclusion of many patients with low-risk disease and by follow-up durations too short to permit detection of any influence of vaginal recurrences on survival.

The purpose of our study was to evaluate the outcome of patients after radical RT for isolated vaginal recurrences of endometrial carcinoma and to determine the clinical and pathologic predictors of outcome.

We reviewed the records of 91 patients treated at our MD Anderson  between 1960 and 1997 with radical RT for vaginal recurrence after definitive surgery for endometrial carcinoma. Thirty-one percent of the patients received external beam RT (EBRT) alone, 12% received brachytherapy alone, and 57% received a combination. The median dose of radiation was 75 Gy (range 34–122). All end points were measured from the time of the first recurrence. The median duration of follow-up after recurrence was 58 months (range 1–289).   Patients who had combined EBRT and brachytherapy received significantly greater total doses than did patients treated with either modality alone (90% > 80Gy)

Results

The 2- and 5-year local control (LC) rate and overall survival rate was 82% and 75% and 69% and 43%, respectively. The median time from initial diagnosis of endometrial cancer to death from disease was 38 months. On univariate analysis, a dose to the relapse site of >80 Gy and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved LC. On multivariate analysis, only the type of treatment correlated significantly with LC (p = 0.03). On univariate analysis, Grade 1 or 2 vs. Grade 3 tumor and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved overall survival.

This study describes one of the largest published experiences of patients treated for isolated vaginal recurrence of endometrial cancer. It confirms that excellent LC rates can be achieved with RT and suggests that the best results are achieved when high doses of radiation are given using a combination of EBRT and brachytherapy. However, the results also suggest that vaginal recurrences are often followed by the development of metastatic disease and that prevention of vaginal recurrence should be a goal of the initial treatment of endometrial cancer.

A number of factors have been correlated with LC. Several authors have reported a relationship between the size of the recurrent tumor and LC . In a series described by Greven and Olds , 6 of 7 tumors <2 cm in size were controlled locally compared with only 2 of 10 tumors >2 cm. Wylie et al. reported a 5-year LC rate of 80% in patients with tumors <2 cm compared with 54% in patients with larger tumors (p = 0.04). In our series, 63% of the patients had tumors <2 cm; however, LC did not correlate with tumor size and was excellent (about 80%) for patients with small or large tumors.

Several authors have reported correlations between the location of the vaginal recurrence and LC. Curran  and Aalders found that apical recurrences had a better response to treatment than more distally located lesions. However, Phillips and Poulsen found that distally located recurrences had a better outcome, and other authors  did not find any significant correlation between recurrence site and outcome. These differences may reflect variations in the methods of treatment and in the types of tumors included in the various studies. For example, in the study by Poulsen , patients with lesions in the distal third of the vagina were more frequently treated with definitive intent than were patients with upper vaginal recurrences (67% vs. 25%). All the patients in our study were treated with curative intent, and we found no significant correlation between the site of recurrence in the vagina and LC.

Curran  reported that patients who received >60 Gy had significantly better survival and pelvic control rates than did patients who received lower doses. In another study, by Wylie, a trend toward better LC was noted in patients who received >80 Gy compared with those who received <80 Gy . The median radiation dose in our study was 74 Gy; patients who received at least 80 Gy had a significantly better LC rate than did patients who received <80 Gy (p = 0.04), although the radiation dose did not correlate with OS. Sears found that patients who had EBRT followed by a brachytherapy boost had the best overall LC rate , a correlation that was also significant on multivariate analysis . We also found that patients who received a combination of EBRT and brachytherapy had better LC and OS rates than did patients who received a single modality (p = 0.01 for LC and p = 0.02 for OS). In a multivariate analysis of LC, the type of treatment was the only significant predictor of outcome; however, the higher doses of radiation delivered to the tumor in patients who received combined treatment probably contributed to their better LC rate. However, in patients who had previously been treated with EBRT to the pelvis, brachytherapy alone may be the only choice, but if the lesion is just outside the previous field, treating with some EBRT before the brachytherapy procedure, with a small overlap, may be beneficial.

Other factors that have been correlated with outcome after an initial recurrence are the time to initial recurrence and the grade of the primary lesion. Most authors have reported a better prognosis for patients who had relatively late recurrences. However, like several other authors , we did not detect such an association. Some authors have reported an association between high tumor grade and poor outcome. Hart) reported that patients with Grade 2–3 tumors had a significantly lower OS rate and poorer LC   than did patients with Grade 1 tumors. In our series, local recurrences were rare and were unassociated with primary tumor grade; however, patients with Grade 3 primary tumors had a significantly lower survival rate than did patients with Grade 1 or 2 tumors. This appeared to reflect a higher rate of distant metastases in patients with Grade 3 tumors.

Despite the excellent LC rate achieved with RT in patients with recurrent endometrial carcinoma (5-year LC rate 75%), the disease-free survival rate at 5 years was still only 45%. Ultimately, 22 patients in our study (24%) developed distant metastases despite LC of their disease; 18 of these patients died with uncontrolled disease. However, in some cases, the time from initial diagnosis of endometrial cancer to death from disease was quite long. Overall, the median time from initial diagnosis to death from endometrial cancer was 38 months. This has implications for studies of adjuvant RT—long follow-up may be necessary to reveal the impact of prevention of vaginal recurrence on OS. Two recent randomized trials have studied the effectiveness of RT in patients with a low to intermediate risk of recurrent endometrial carcinoma. The Post Operative Radiation Therapy in Endometrial Cancer study demonstrated a reduction in local recurrences from 14% in patients who did not receive pelvic RT to 4% in patients who did; however, the difference in the OS rate was not statistically significant. A similar result has been reported for a Gynecologic Oncology Group study of adjuvant pelvic RT for intermediate-risk endometrial cancer, although the study probably had inadequate power to detect absolute survival differences of <10–15%. It has been suggested that in these studies, successful salvage treatment for vaginal recurrences prevented adjuvant RT from having an impact on OS. Details of the Gynecologic Oncology Group trial have not yet been published. However, the duration of follow-up in the Post Operative Radiation Therapy in Endometrial Cancer trial may have been too short to permit complete evaluation of the impact of vaginal recurrence on outcome. In that study, the 2-year survival rate of 51 patients with vaginal recurrence was 79%. This salvage rate appeared to be excellent and is similar to our 2-year survival rate of 69%; however, by 5 years, the OS of our patients had fallen to 43%. RT produces excellent LC rates in patients with isolated vaginal recurrence of endometrial carcinoma (5-year LC rate 75%). However, because of later distant metastases, only about 45% of patients with isolated vaginal recurrence survive >5 years. The OS rate is related to the grade of the primary tumor and the type of treatment used for the recurrent tumor. The LC rate is related to the dose of radiation applied to the recurrent tumor and the type of treatment used, with combination treatment (EBRT plus brachytherapy) more effective than either EBRT or brachytherapy alone.