The Role of Adjuvant Radiation in Endometrial Cancer
The Role of Adjuvant Radiation in Endometrial Cancer
ABSTRACT: Endometrial cancer treatment ideally begins with a staging procedure including abdominopelvic washing, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymph node evaluation. Recommendations for postoperative adjuvant radiotherapy are determined by recurrence risk. Patients who have undergone staging and have early stage I disease and an absence of high-risk features for recurrence generally are treated with surgery alone. Intermediate-risk patients—those with high-risk stage I disease and some stage II patients—may benefit from adjuvant radiation therapy. Several randomized trials show that radiation therapy improves locoregional control among intermediaterisk patients. The optimal type of radiation therapy, whether vaginal brachytherapy or whole-pelvic radiation therapy, remains undetermined, though treatment decision can be guided by risk factors not encompassed by the current staging system. Patients with high-risk stage II disease and stage III disease generally receive external-beam radiotherapy, often in combination with chemotherapy. Chemotherapy alone in advanced-stage patients is a consideration, given the results of the Gynecologic Oncology Group (GOG)-122 trial.
Endometrial cancer is the most common gynecologic malignancy, with an estimated 40,100 cases and 7,470 deaths in 2008. This malignancy represents 6% of all cancers, and 3% of cancer deaths in women. Endometrial cancer is more prevalent in older women, with an incidence of 1 in 142 for women 40 to 59 years old, increasing to 1 in 81 women over 70 years old. Median age at diagnosis is 62. The mortality of endometrial cancer has decreased from 4.18 to 4.12 per 100,000 from 1991 to 2004. Risk factors for endometrial cancer include early age at menarche, late age at menopause, nulliparity, obesity, diabetes, and hypertension. Incidence of uterine cancer decreased by 1.6% per year from 1975 to 1991, and decreased by 0.1% per year between 1991 and 2005.
The general treatment approach to endometrial cancer therapy includes hysterectomy, salpingo-oophorectomy, and abdominopelvic washings (with or without lymph node dissection) as the primary therapy, with the use of postoperative radiation therapy (including vaginal brachytherapy, external- beam pelvic radiation therapy, extended-field irradiation, and wholeabdomen radiation therapy), hormonal therapy, and chemotherapy depending on pathologic criteria and patient-related factors.
After surgical and pathologic staging is complete, patients can be roughly stratified into treatment groups based on risk. The first group—patients at low risk—includes those who have a high probability of cure and a low risk of recurrence without any additional treatment. The second group—patients with an intermediate risk—consists of those who have a higher rate of recurrence and lower rate of cure but who may or may not benefit from adjuvant radiation therapy. The third group—those at high risk—includes patients with a high recurrence rate for whom both chemotherapy and radiotherapy can be utilized to improve outcomes.
Low-risk patients are those with disease confined to the uterus and no adverse risk factors for recurrence, with no or little myometrial invasion of the tumor, and who have grade 1 or 2 histology. These patients have been shown to have an excellent cure rate without additional therapy.
A prospective study of patterns of failure for early-stage disease was conducted between 1977 and 1983 (Gynecologic Oncology Group [GOG] protocol no. 33). The investigators found no recurrences among 72 patients with grade 1 and 2 tumors with no myometrial invasion who did not receive radiation therapy. Another study showed only one recurrence after surgery alone in 127 patients with noninvasive cancer. The diagnosis of “recurrence” was clouded by the finding of an anaplastic carcinoma on the pelvic side wall in a patient who had initially presented with a grade 1 endometrioid adenocarcinoma, which the authors believed may have been a second primary. Another study of patterns of recurrence with surgery alone noted vaginal recurrence rates of 4.4%, 5.7%, and 13.6% for normal, intermediate, and anaplastic histology, respectively.
When stratifying by depth of invasion, recurrences were noted to be 3.7% with no myometrial invasion, 4.7% with superficial invasion, and 15.1% with deep invasion. In the GOG-99 study, low-intermediate risk patients had a 4-year isolated local relapse rate of 5%. Other investigators have described similar results with surgery alone in similar groups of low-risk patients.[8,9] Given the limited benefit, the risks and costs of adjuvant therapy are probably not warranted in this group.
Intermediate-risk patients consist of those with disease confined to the uterus but who have a higher risk of recurrence based on patient- and tumor-related characteristics. These characteristics include age, lymphovascular space invasion (LVSI), and tumor size. Treatment recommendations are most varied in this group of patients, as seen in the National Comprehensive Cancer Network (NCCN) guidelines for cancer treatment.
Several important risk factors for recurrence are not encompassed by our current staging system, including patient age, LVSI, and tumor size.[11-14] Younger women with endometrial cancer generally have a better prognosis. In an analysis of the GOG protocol 33 patients, 5-year relative survival rates were 96.3% for patients 40 years old or younger, 94.4% for patients 41 to 50 years old, 87.3% for patients 51 to 60 years old, 78% for patients 61 to 70 years old, 70.7% for patients 71 to 80 years old, and 53.6% for patients older than 80. Another study estimated that for every 1-year increase in age, the recurrence risk increases by 7%.
LVSI is an independent risk factor for recurrence and death from all types of endometrial cancer. Five-year survival in high-risk patients with endometrial cancer is 83.5% when considering those without LVSI, but only 64.5% in those with LVSI. Tumor size has also correlated with lymph node metastases. Metastatic disease was noted in 4% of patients with tumors ≤ 2 cm, but 15% in patients with tumors > 2 cm, and 35% of patients with tumors involving the entire uterine cavity.
Five prospective randomized trials (Table 1) have attempted to delineate the role of adjuvant radiation therapy for intermediate-risk endometrial cancer.
• Norwegian Trial—The first of these randomized studies was the Norwegian trial by Aalders et al, which was published in 1980. A total of 540 women with clinical stage I endometrial cancer who underwent hysterectomy and postoperative vaginal brachytherapy (60 Gy to the vaginal mucosal surface) were randomized to additional pelvic radiation therapy (40 Gy with a midline block after 20 Gy) or observation. Pelvic radiation decreased vaginal and pelvic relapse rate (7% in the control group vs 2% in the pelvic radiation group at 5 years). However, the rate of distant metastases was higher in the pelvic radiation group (5% in the control group compared to 10% in the pelvic radiation group at 5 years), and the overall 5-year survival rate was not statistically different (89% vs 91%). On subset analysis, the patients with grade 3 tumors and > 50% myometrial invasion had non–statistically significant improvements in local control and survival after pelvic radiation therapy (18% vs 27% of deaths due to cancer).
• PORTEC-1 Trial—The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial was a randomized trial of surgery and postoperative radiation therapy vs surgery alone in 714 patients with stage I endometrial cancer. Patients had stage IA, grade 2/3; stage IB, grade 2/3; or stage IC, grade 1/2 disease. Lymph node sampling was not routinely performed, though suspicious lymph nodes were biopsied. Radiation therapy was given to a total dose of 46 Gy in 2-Gy fractions, with 177 patients treated with a four-field technique and 101 patients treated with anteroposterior/ posteroanterior (AP/PA) opposed fields. The 5-year locoregional relapse rates were 4% in the radiation therapy group and 14% in the group receiving no further treatment (P < .001).
In an update of the study results with central pathology review, 10- year actuarial locoregional recurrence rates were 5% and 14%, respectively (P < .001), also favoring the radiation therapy group. The majority (75%) of locoregional recurrences in the observation arm were noted to be in the vagina or the vaginal vault. Risk factors for locoregional relapse were depth of invasion (less or more than half of the myometrium; P = .07), age (< 60, 60–70, and > 70; P = .007), International Federation of Gynecology and Obstetrics (FIGO) grade (P = .005), and radiation therapy (P < .0001). The investigators found no difference in overall survival. Five-year grade 3/4 toxicity rates were 3% in the radiation therapy group and 0% in the control groups. Complication rates were improved in patients treated with a 4-field technique compared to those treated with an AP/PA technique. The authors concluded that postoperative radiation therapy was not recommended in stage I patients less than 60 years old and patients with grade 2 tumors with superficial invasion.