We commend Chen et al for their comprehensive review of the evaluation and treatment of endometrial cancer. As the authors state, endometrial cancer is the most common gynecologic malignancy in the United States. Fortunately, it is also one of the most curable. The majority of women with endometrial cancer are treated by surgery alone; primary radiation therapy is generally reserved for patients with unacceptable risks of surgical morbidity. In this commentary, we will address several areas of current controversy.
Pelvic and Para-aortic Lymphadenectomy
A review of data from the National Cancer Institutes Surveillance, Epidemiology and End Results (SEER) program on more than 10,000 women with stage I or II endometrial cancer demonstrated that performance of lymph node sampling does not appear to confer an overall survival benefit. However, lymph node sampling was associated with increased survival among women with stage I, grade 3 disease. This increase in survival likely reflects the accurate differentiation of true stage I patients with no lymph node metastases from those who are true stage III patients but do not undergo lymph node sampling.
The purpose of lymphadenectomy in the staging of endometrial cancer is to more accurately estimate prognosis and to determine whether adjuvant therapy is indicated. As suggested by the SEER data, women without obvious evidence of extrauterine disease at the time of surgery are most likely to benefit from evaluation of the lymph nodes. Intraoperative identification of patients at risk for lymph node metastases is crucial because lymphadenectomy would unnecessarily increase the time and morbidity of surgery if the procedure were performed for every woman with endometrial cancer.
In Table 4 of their review, Chen et al present their indications for pelvic and/or para-aortic lymphadenectomy. Their criteria for the performance of pelvic lymphadenectomy are widely accepted. In a large Gynecologic Oncology Group (GOG) study, Morrow et al clearly demonstrated that 98% of para-aortic metastases can be identified when lymphadenectomy is restricted to patients with grossly positive pelvic nodes, grossly positive adnexal metastases, or invasion of the outer one-third of the myometrium. These findings suggest that the criteria proposed by Chen et al for the inclusion of para-aortic lymphadenectomy may be too broad.
Surgeons with expertise in the management of endometrial cancer should be available at the time of hysterectomy to ensure removal of a sufficient quantity of nodal tissue in patients at risk for metastases. Reliable proof of the absence of extrauterine disease can prevent the unnecessary use of adjuvant therapy.
Postoperative Radiation Therapy
In the classic study by Aalders et al, 540 women with clinical stage I endometrial cancer were randomized to external pelvic irradiation (teletherapy) or no further therapy following surgery and intravaginal irradiation (brachytherapy). Postoperative teletherapy decreased the risk of vaginal and pelvic recurrences, but survival was not improved due to the increased risk of distant metastases. Chen et al acknowledge that the optimal role of postoperative brachytherapy and teletherapy in the management of endometrial cancer is still undefined.
Adjuvant radiotherapy is commonly used in high-risk patients without documented extrauterine spread, and yet Larson et al have reported that such patients still have an excellent prognosis when treated by surgery alone. They conclude that, in patients without extrauterine disease, ...the role of adjuvant radiotherapy in patients with endometrial cancer who are surgically staged appears to be nonexistent, and the routine administration of adjuvant radiotherapy to these patients should be abandoned.&ldots;
The risk of morbidity without a survival benefit in patients treated with postoperative external-beam radiotherapy is worth emphasizing. Two patients died from radiation-related complications in the study of Aalders et al. Morrow et al reported a tenfold increase in the rate of complications among clinical stage I or II patients who received external-beam radiation, as compared with those treated with implants alone. In addition to short-term complications, partial-body radiotherapy for endometrial cancer is associated with a small, long-term increase in the risk of developing leukemia.
The benefit of postoperative external-beam radiotherapy appears to be minimal in women with stage I or II endometrial carcinoma who undergo adequate surgical staging. However, postoperative pelvic teletherapy does appear to benefit patients with documented pelvic lymph node metastases. Extended-field radiotherapy has a significant complication rate but does improve survival in patients with para-aortic lymph node metastases.
Newer Treatment Strategies
Molecular characterization of the initiation, promotion, and progression of endometrial cancer may pave the way for new approaches to the management of advanced and recurrent disease. Such molecular markers as p53, Ki-67, and others have been shown to have a prognostic impact. In addition to identifying tumors at risk for recurrence, molecular histologic analysis may be used to define a subgroup of patients who would benefit from adjuvant therapy.
Understanding the molecular pathogenesis of endometrial carcinoma is a prelude to the implementation of novel therapeutic approaches. Restoration of tumor-suppressor gene function and/or suppression of oncogene activity may eventually be useful treatment options. In addition, the specificity of monoclonal antibodies and their conjugates have far-reaching clinical implications due to their ability to focus immune mechanisms of the host or cytotoxic agents on dividing tumor cells.
Molecular characterization of endometrial cancer is still in its infancy. To date, the clinical usefulness of a molecular-based therapeutic approach has been hampered by toxicity and the lack of effective transmission vectors. Until such treatments are available, patients with advanced or recurrent endometrial carcinoma should be encouraged to participate in ongoing clinical investigations.