UPDATE: ENDOMETRIAL CANCER
Are lymphadenectomy and external-beam radiotherapy valuable in women who have an endometrial malignancy? Debate over the standard of care continues.
IN THIS ARTICLE
Dr. Mutch reports that he has received grant or research support from Lilly and Genentech. He serves as a speaker for GSK, Lilly, and Merck. Dr. Rimel reports no financial relationships relevant to this article.
Endometrial cancer is a great concern in industrialized nations, where it is the most common gynecologic cancer—with incidence increasing every year. Survival is generally very good for women who have low-grade disease confined to the uterus. However, for patients who have high-grade disease, an aggressive histologic type, or other features that suggest a poor prognosis, the cure rate approaches 75%. 1
Primary surgery is the mainstay of initial treatment and basis of FIGO staging ( TABLE ), which requires:
- total hysterectomy
- bilateral salpingo-oophorectomy
- complete examination of the abdomen
- pelvic washings
- lymph-adenectomy (anatomic boundaries and node counts aren’t specified).
Controversy clouds our understanding of the optimal type of surgery, utility of pelvic lymphadenectomy, and possible benefit of adjuvant radiation therapy. During the past year, fuel has been added to this debate:
- Two randomized, controlled trials of surgery with and without pelvic lymphadenectomy in early-stage patients demonstrated no survival benefit. Earlier studies investigating the benefits of lymphadenectomy in endometrial cancer have been largely retrospective, and results have varied.
- A concurrent randomized, controlled trial of external-beam radiotherapy for women who have intermediate- or high-risk disease showed no improvement in overall survival, although local control increased by 3%.
FIGO surgical staging for endometrial cancer
Tumor is confined to uterine fundus
Tumor is limited to endometrium
Tumor invades less than half of the myometrial thickness
Tumor invades more than half of the myometrial thickness
Tumor extends to cervix
Cervical extension is limited to endocervical glands
Tumor invades cervical stroma
There is regional tumor spread
Tumor invades uterine serosa or adnexa, or cells in the peritoneum show signs of cancer
Vaginal metastases are present
Tumor has spread to lymph nodes near the uterus
There is bulky pelvic disease or distant spread
Tumor has spread to bladder or rectum
Distant metastases are present
ASTEC study group, Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373:125–136.
Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100:1707–1716.
Among the arguments for lymphadenectomy in endometrial cancer staging are:
- It aids in the selection of women for radiation or other adjuvant treatment
- It may have a direct survival benefit, as suggested by retrospective studies.
But lymphadenectomy is time-consuming, requires a specialized gynecologic surgeon, and is associated with some increase in the risk of morbidity—namely, lymphedema, lymphocyst formation, deep-vein thrombosis (DVT), and blood loss.
The much-anticipated report of the 85-center, multinational ASTEC trial [ A S urgical T rial of E ndometrial C ancer], published earlier this year, offers further insight into the practice of lymphadenectomy. ASTEC involved two randomizations: The first, to pelvic lymphadenectomy; the second, to radiation therapy.
The ASTEC trial enrolled 1,408 women who had histologically confirmed endometrial carcinoma that was believed to be confined to the uterus. How this determination was made was not specified. Patients who had enlarged lymph nodes corroborated by computed tomography or magnetic resonance imaging were not excluded.
Participants were randomized to either of the following treatment groups:
- traditional surgery with total hysterectomy and bilateral salpingo-oophorectomy, pelvic washings, and palpation of para-aortic nodes
- the same surgery plus systematic lymphadenectomy of the iliac and obturator nodes.
If any para-aortic nodes were suspicious, biopsy or lymphadenectomy was performed at the discretion of the surgeon ( FIGURE ).
FIGURE Nodes reveal when cancer has spread
Women in the ASTEC trial were randomized to traditional surgery (total hysterectomy and bilateral salpingo-oophorectomy), pelvic washings, and palpation of para-aortic nodes or to the same surgery plus lymphadenectomy of the iliac and obturator nodes.
Operative findings determined a patient’s level of risk
After surgery, patients were categorized as having one of the following:
- low-risk, early-stage disease. This group included patients who had disease classified as stage IA or IB, grade 1 or 2. They were deemed to have a suitably low risk of recurrence to be offered further treatment according to their physician’s standard practice.
- intermediate- or high-risk, early-stage disease. These patients were randomized to the ASTEC radiation-therapy trial, which compared external-beam radiotherapy with no external-beam radiotherapy. The authors assert that this second randomization was necessary to prevent over- or undertreatment of patients who had unknown node status, which might alter survival outcomes.
- advanced disease. These patients were referred to their physician for further treatment.
In both surgical groups (with and without lymphadenectomy), approximately 80% of patients had disease confined to the uterus. Nodes were harvested in 91% of the patients in the lymphadenectomy group, compared with 5% of patients in the traditional-surgery group. Nine percent of women in the lymphadenectomy group had positive nodes.
The authors observe that more women had deeply invasive disease and adverse histologic types in the group that underwent lymphadenectomy. There were no differences between the two groups in overall survival; disease-specific survival; recurrence-free survival; or recurrence-free, disease-specific survival, after adjustment for baseline differences. Subgroup analysis for low-risk, high-risk, and advanced disease also failed to demonstrate differences in overall survival and recurrence-free survival.
Study from Italy produces similar findings
An independent randomized, controlled trial examining survival outcomes for endometrial cancer patients with and without lymphadenectomy was released by the Italian group in late 2008. In this study, 537 patients who had histologically confirmed endometrial carcinoma believed to be confined to the uterus were randomized to total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic lymphadenectomy.
Anatomic boundaries of the pelvic lymph-node dissection were clearly defined, and a minimum lymph-node count of 20 was specified for inclusion. Intraoperative frozen section was utilized to exclude patients who had grade-1 disease that was less than 50% invasive. The option of para-aortic lymph-node dissection or sampling was left to the discretion of the surgeon. If pelvic nodes were larger than 1 cm, they were removed or sampled regardless of randomization.
Unlike the ASTEC trial, this study did not attempt to control adjuvant treatment. Patients were treated according to the discretion of the physician. Most patients received no further therapy; only 20% underwent radiation therapy, and 7% received chemotherapy.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Given the findings of these two, large, multi-institutional trials with strikingly similar results but major problems, what is a gynecologist to do? Can lymphadenectomy be avoided in patients whose disease is believed to be confined to the uterus?
For now, the answer is a tentative “No.”
There appears to be no survival advantage to removal of lymph nodes when disease is confined to the uterus, but that is not to say there is no benefit to systematic lymphadenectomy—just that there is no survival benefit afforded by the procedure. Benefits of lymphadenectomy, which include more precise definition of the extent of disease, minimization of over- or undertreatment, and a reduction in overall treatment and cost, still remain. The concept of surgical debulking put forward by Bristow and coworkers still has merit, and any gross disease should be removed, if feasible. 2
Lymphadenectomy in endometrial cancer remains controversial and complex, especially as we lack a precise method for determining which patients will have nodal disease. Our practice remains to remove the lymph nodes whenever possible to better tailor any adjuvant treatment.—DAVID G. MUTCH, MD; B. J. RIMEL, MD
Women in the lymphadenectomy group were more likely to have stage-IIIC disease, which is directly attributable to histologic evaluation of the lymph nodes in this group. The authors point out that these patients had more accurate assessment of their prognosis, allowing for the tailoring of adjuvant treatment.
The overall survival and disease-free survival curves for the two experimental groups were similar, consistent with data from the ASTEC trial. This proved to be true for both the intention-to-treat and according-to-protocol groups. The authors note that their results are similar to those of the ASTEC trial, despite the significant difference in the number of nodes removed in each trial.
Some aspects of the trials hamper interpretation and comparison
Outcomes are improved when surgery is performed by a trained gynecologic oncologist. In the ASTEC trial, each lymphadenectomy was performed by a specialized gynecologic surgeon who was “skilled in the procedure.” In the Italian study, the type of surgeon was not specified, but the specific anatomic boundaries of the dissection and the minimum node count were. More specific data are needed before any conclusions can be drawn about the effect of surgical skill on outcome in these trials.
In the ASTEC trial, 9% of patients in the lymphadenectomy group had no nodes removed, and more than 60% of patients would not have met criteria for inclusion in the lymphadenectomy arm of the Italian study—suggesting that the majority of women in the ASTEC trial had inadequate lymphadenectomy. Para-aortic lymphadenectomy was left to the discretion of the attending surgeon, and some patients did have resection of these nodes. The data do not include information about whether these patients were treated in the para-aortic region based on the histology of these nodes.
Randomization in a prospective study is supposed to equalize the risks between groups. In the ASTEC trial, despite randomization, there were 10% more patients who had deeply invasive disease in the lymphadenectomy group, along with 3% more adverse histologies and high-grade (grade-3) tumors. Given the higher incidence of positive nodes and poorer outcome in these cases, this difference may have had a significant impact on the evaluation of the groups for overall or disease-specific survival.
ASTEC/EN.5 Study Group, Blake P, Swart AM, Orton J, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009;373:137–146.
Radiation therapy has been a standard treatment for endometrial cancer when there is high risk of recurrence. This report combines two independent randomized, controlled trials investigating the benefit of postoperative adjuvant pelvic radiation in women who had early-stage disease and who met histologic criteria for high risk of recurrence and death. The trials are the EN.5 trial from Canada, and the radiation-therapy randomization of the ASTEC trial). Neither found a benefit in terms of overall survival, disease-specific survival, or recurrence-free survival, although local recurrence was reduced by 2.9% The authors also provide a review of the literature and a meta-analysis of other randomized, controlled trials on this subject.
Details of the EN.5 and ASTEC radiation-therapy trials
Criteria for enrollment were similar for the two trials, which focused on women who had histologically confirmed endometrial cancer and an intermediate or high risk of recurrence. This included women who had FIGO stage IA or stage IB (grade 3), stage IC (all grades), or papillary serous or clear-cell histology (all stages).
WHAT THIS EVIDENCE MEANS FOR PRACTICE