Journal of the National Cancer Institute Advance Access published online on November 25, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn413
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© The Author 2008. Published by Oxford University Press.
EDITORIALS |
Lymphadenectomy's Role in Early Endometrial Cancer: Prognostic or Therapeutic?
Affiliations of authors: Women's Cancer Research Institute, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA (CSW, BYK)
Correspondence to: Beth Y. Karlan, Women's Cancer Research Institute, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, #290W, Los Angeles, CA 90048 (e-mail: karlanb{at}cshs.org).
In 1988, endometrial cancer became a surgically staged disease. Because frequent inaccuracies in clinical staging were recognized, the International Federation of Gynecology and Obstetrics introduced a new surgicopathologic staging system that emphasized the prognostic value of surgical staging information (1). Largely on the basis of the seminal findings of the Gynecologic Oncology Group (GOG) 33 trial (2), surgical staging was introduced that incorporated pathological risk factors to better define the extent of disease, estimate prognosis, and guide adjuvant treatment recommendations. Despite implementation of this more accurate staging system, optimal treatment for the management of endometrial cancer remains controversial, particularly in patients with intermediate-risk disease, which is defined as corpus-confined tumors with high-risk features (high tumor grade, deep myometrial invasion, cervical extension, and serous or clear cell histology). At the heart of this debate are the therapeutic roles of lymphadenectomy and adjuvant radiation.
The pelvic lymph nodes are the most common site of extrauterine disease. By current standards, endometrial cancer should be primarily treated through a surgical approach that includes cytologic washings (ie, fluid from the pelvic cavity), extrafascial hysterectomy, bilateral salpingo-oophorectomy, and selected pelvic and para-aortic lymphadenectomy in patients with high-risk uterine features (1). Since this recommendation two decades ago, a debate surrounding the extent of surgical staging has ensued and the pendulum has swung toward routine comprehensive surgical staging for the majority of patients with endometrial cancer.
There is no argument that the risk of extrauterine disease increases with increasing tumor grade and myometrial invasion and that these factors negatively impact survival. The inaccuracies of the preoperative and intraoperative assessments of these pathological parameters along with the inability of palpation to identify lymph node metastases have been cornerstones of the argument for routine surgical staging. Lymph node dissection can be accomplished safely in experienced hands, and knowledge of the lymph node status provides for more accurate prognosis and treatment planning. In several retrospective analyses, surgical staging appeared to be of therapeutic value, with improved survival outcomes for patients who underwent lymphadenectomy compared with those who did not (2,3). The current recommendation of the American College of Obstetricians and Gynecologists (4) and the National Comprehensive Cancer Network (5) is to perform a complete staging procedure, including bilateral pelvic and para-aortic lymphadenectomy, on most women with endometrial carcinoma. Exceptions to this recommendation are young and/or perimenopausal women with low-grade endometrial carcinomas arising out of atypical hyperplasia, women with increased risk of mortality due to comorbidities, and women with medical or technical contraindications to lymph node dissection.
Fueling the controversy surrounding lymphadenectomy are two large randomized controlled trials that have found no survival benefit but added toxicity when adjuvant radiation therapy is delivered to patients with intermediate-risk endometrial cancer. The Postoperative Radiation Therapy in Endometrial Cancer trial (6) and GOG 99 trial (7) differed slightly in eligibility criteria and design, but both confirmed a statistically significant decrease in pelvic recurrences (mostly at the vaginal cuff) that did not translate into a survival benefit with the addition of adjuvant radiation. There was greater toxicity in the radiation treatment arms of both trials, and we have come to recognize that the majority of patients with early stage endometrial cancer have been overtreated with adjuvant radiation.
It is in this context that we are now presented, in this issue of the Journal, with the results of the randomized clinical trial by Panici et al. (8), who examined the role of systemic pelvic lymphadenectomy vs no lymphadenectomy in early stage endometrial carcinoma. In this multicenter Italian trial, patients with endometrioid or adenosquamous endometrial carcinoma underwent surgery with frozen-section analysis of the uterus. Those with confirmed myometrial invasion (stages IA and stage IB with grading 1 were excluded) were randomly assigned to systemic pelvic lymphadenectomy (with removal of at least 20 lymph nodes, n = 264) versus no lymphadenectomy (n = 250). Para-aortic lymph node assessment and adjuvant treatment recommendations were left to the discretion of the treating physicians. At a median follow-up time of 49 months, this trial found no differences in disease-free or overall survival between the two arms. Although the patient characteristics in this trial are slightly out of balance, favoring improved survival in the no-lymphadenectomy arm (46% stage IA or IB in the no-lymphadenectomy arm vs 33% in the lymphadenectomy arm), this level I evidence (from a randomized controlled trial) is consistent with findings of A Study in the Treatment of Endometrial Cancer trial (9)—a British randomized controlled trial that also found no survival benefit associated with pelvic lymphadenectomy in early stage endometrial cancer.
Panici's trial also addressed other possible pros and cons of lymphadenectomy. Lymphadenectomy more accurately identified metastatic spread and disease stage (13% detection of lymph node metastases in the lymphadenectomy arm vs 3% in the no-lymphadenectomy arm). Despite a statistically significantly longer operating time and a slightly longer length of stay in the hospital in patients in the lymphadenectomy arm, there were no differences in estimated blood loss or rates of blood transfusion. The rate of intraoperative complications was similar in both arms, but both early and late postoperative complications occurred more frequently in the lymphadenectomy arm, largely due to the development of lymphocysts and lymphedema. There were no statistically significant differences in the use of adjuvant treatment, with no further treatment administered to 69% in the lymphadenectomy arm and 65% in the no-lymphadenectomy arm. Although not statistically significantly different, the types of adjuvant treatment differed slightly between the two arms, with more chemotherapy and less radiation therapy being used in the surgically staged patients. The authors conclude that, although a survival benefit could not be demonstrated, lymphadenectomy maintains its importance in determining a patient's prognosis and tailoring adjuvant therapies.
So, where are we now? Endometrial cancer care is rapidly evolving toward more personalized treatment recommendations to improve outcome and minimize toxicity and cost. But do these new findings obviate the need for lymph node assessment in early stage endometrial cancer? Without a demonstrable survival benefit, the answer to this question comes down, in part, to one's personal philosophy. We have level I evidence demonstrating that neither pelvic lymphadenectomy nor adjuvant radiation therapy confers any survival benefit in early stage endometrial cancer. These results bust the myth that is based on previous retrospective studies that lymphadenectomy, in and of itself, provides therapeutic benefit and survival advantage in endometrial cancer. Yet, this trial continues to support the notion that lymphadenectomy can provide important prognostic information and can help guide adjuvant treatment recommendations.
REFERENCES
1. Pecorelli S, Ngan HY, Hacker N. Cancer of the corpus uteri. In: Staging Classification and Clinical Practice Guidelines for Gynecological Cancers (2000) Amsterdam, the Netherland: Elsevier. 63–83.
2. Kilgore LC, Partridge EE, Alvarez RD, et al. Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol (1995) 56:29–33.[CrossRef][Web of Science][Medline]
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4. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol (2005) 106:413–425.[Medline]
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6. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet (2000) 355:1404–1411.[CrossRef][Web of Science][Medline]
7. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol (2004) 92:744–751.[CrossRef][Web of Science][Medline]
8. Panici PB, Basile S, Maneschi F, et al. Systemic pelvic lymphadenectomy vs no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst (2008) 100(23)):1707–1716.
9. Kitchener H, Group AS. ASTEC—A Study in the Treatment of Endometrial Cancer: a randomised trial of lymphadenectomy in the treatment of endometrial cancer (Abstract). Gynecol Oncol (2006) 101:S21–S22.
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J Natl Cancer Inst 2008 100: 1657.
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