The American Cancer Society estimates that 22,220 women will be diagnosed with ovarian cancer during 2005.1 Of these, approximately 25% will be diagnosed with early-stage disease. Standard therapy for all women with ovarian cancer includes a staging procedure with lymphadenectomy.2,3 Because patients with ovarian metastases to the lymph nodes have poorer outcomes, lymphadenectomy plays a role in assessing their prognosis and determining their need for adjuvant treatment. The observation that the number of pathologically negative nodes in the permanent specimen is correlated with survival has been shown in melanoma, breast, and colorectal cancers.4–8
Nonetheless, many women with early-stage ovarian cancer are inadequately staged, and surgeons with the expertise to perform a lymphadenectomy and a complete staging procedure are not always involved during the initial surgery.9,10 Comprehensive staging surgeries often upstage women presumed to have early-stage disease.11–13 In fact, a recent study by Cass et al14 found that 15% of patients with clinical stage I disease have positive lymph nodes. Previous studies looking at early-stage cancers suggest that inadequate staging leads to decreased survival, but these studies have been limited by small numbers of women.15,16 Furthermore, they did not focus on the significance of lymphadenectomy associated with staging surgery. Complete staging is also important in ovarian cancer because some patients with stage IA/B grade 1 disease may not require adjuvant chemotherapy, whereas others with high-risk disease need additional treatment.17,18 Aside from the prognostic treatment implications of staging procedures, the potential therapeutic benefits of a lymphadenectomy in early-stage ovarian cancer have not been adequately addressed.
The objectives of our study were to estimate the survival impact of lymphadenectomy in women diagnosed with clinical stage I ovarian cancer and to identify the important demographic and clinicopathologic prognostic factors in stage I ovarian cancer.
PARTICIPANTS AND METHODS
Demographic, clinicopathologic, treatment, and survival information of women diagnosed with stage I ovarian cancer from January 1, 1988, through December 31, 2001, was extracted with permission from the Surveillance, Epidemiology and End Results (SEER) program of the United States National Cancer Institute. These data are representative of approximately 14% of the U.S. population and are reported from 12 population-based registries.19 We divided the registries into three regions: Western, including San Francisco-Oakland, Hawaii, Seattle (Puget Sound), Alaska, San Jose-Monterey, and Los Angeles; Eastern, including Connecticut and metropolitan Atlanta; and Central, including metropolitan Detroit, Iowa, New Mexico, and Utah.
A total of 6,686 women with stage I invasive ovarian cancer were identified after excluding those with borderline tumors. All lymph nodes resected were negative for metastatic disease. To better characterize our patient population, the race classifications of the SEER program were categorized into five groups: Caucasians, Hispanics, African Americans, Asians, and Others. Asians were defined as Chinese, Japanese, Korean, Vietnamese, and Filipina. All other race and ethnicity classifications were defined as Others.
To analyze trends in the study cohort and to estimate 5-year disease-specific survival, χ2 tests and Kaplan-Meier analyses with log-rank tests were performed based on the specified nodal groups. The outcome of interest was death from ovarian cancer and time to death was censored in women who died from causes other than ovarian cancer. Cox proportional hazards were used for multivariable analyses. Two-tailed tests at P values less than .05 were considered significant. All data were analyzed using Intercooled STATA 8.0 (STATA Corporation, College Station, TX) and SAS 6.12 (SAS Inc, Cary, NC).
A total of 6,686 women were identified with stage I invasive ovarian cancer between 1988 and 2001. The demographic and pathologic characteristics are shown in Table 1. Of these, 4,595 (68.8%) women had hysterectomies, and 2,091 (31.2%) did not. Only 2,862 (42.8%) women had a lymphadenectomy as part of their staging procedure. The median number of nodes resected was 9 (range 1–84). All lymph nodes resected were negative for metastatic disease. A significantly greater proportion of younger women (less than 50 years) underwent a lymphadenectomy compared with those aged 50 or older (47.0% versus 39.8%, P<.001). Compared with 42.7% of Caucasians, 47.2% of Hispanics, and 48.8% of Asians, only 32.7% of African-American women underwent a lymphadenectomy (P<.001). Based on geographic region, patients in the Western region had a significantly higher likelihood of receiving a lymphadenectomy than those in the Eastern and Central regions (46.9% versus 39.7% and 38.8%, respectively; P<.001).
Only 42.4% of patients with non–clear cell epithelial cancer had a lymphadenectomy, whereas 56.6% of those with clear cell cancer had a lymphadenectomy (P<.001). Even lower percentages of patients with germ cell tumors, sex cord stromal tumors, and sarcomas had a lymphadenectomy (36.8%, 28.9%, and 39.6%, respectively; P<.001). Of those with grade 3 tumors, 49.9% received a lymphadenectomy, compared with only 45.3% and 47.8% of those with grade 1 and 2 tumors, respectively (P<.001). With each subsequent time period (1988–1992, 1993–1997, and 1998–2001), the percentage of women receiving lymphadenectomy increased from 29.5% to 41.7% to 56.7%, respectively (P<.001).
On Kaplan-Meier analysis, the 5-year disease-specific survival of all women with clinical stage I ovarian cancer who underwent lymphadenectomy was 92.6%, compared with 87.0% for those who did not have a lymphadenectomy (Table 2, Fig. 1). Lymphadenectomy did not improve the survival of patients less than 50 years of age (93.4% compared with 94.1%; P=.52). However, patients aged 50 years or older did benefit from a lymphadenectomy, with an improvement in survival rate from 82.3% to 92.0% (P<.001). The overall survival for those with stage I disease was relatively comparable among Caucasian, Hispanic, African-American, and Asian populations (88.9%, 91.2%, 91.7%, and 89.6%, respectively; P=.64). Caucasian women clearly benefited from undergoing a lymphadenectomy (86.1% versus 92.9%, P<.001). Similar findings were noted in Hispanics, African Americans, and Asians, but these differences were not statistically significant.
Women with non–clear cell epithelial ovarian cancer had a significantly improved 5-year disease-specific survival with lymphadenectomy (85.9% compared with 93.3%; P<.001; Table 2). Clear cell ovarian cancers (83.8% compared with 86.6%; P=.31) and sarcomas (75.9% compared with 87.1%; P=.14) did not show a statistically significant benefit toward better survival associated with lymphadenectomy. In addition, germ cell (P=.55) and sex cord stromal tumors (P=.97) showed no improvement in survival associated with lymphadenectomy. Although no statistical benefit from lymphadenectomy was detected in those with grade 1 (94.7% without lymphadenectomy versus 96.4% with lymphadenectomy; P=.08) and grade 2 (91.1% versus 93.6%; P=.18) disease, those with grade 3 disease showed a significant survival increase from 74.4% to 88.8% (P<.001).
Of the women who underwent a lymphadenectomy, the median number of nodes resected was nine (range 1–84). To estimate the potential benefits of an extensive lymphadenectomy in stage I ovarian cancer, we divided our patient cohort into three groups, those who had 0 nodes, those with fewer than 10 nodes, and those with 10 or more nodes resected (Table 3). The extent of node resection (0, fewer than 10, and 10 or more) increased the survival of patients with stage IC disease from 72.8% to 86.7% to 90.1% (P<.001), with a nonstatistical improvement in stages IA and IB disease. In patients with non–clear cell epithelial carcinoma, the extent of node resection was associated with improved 5-year disease-specific survivals of 85.6%, 93.3%, and 93.5%, respectively (P<.001). Although there was a nonsignificant improvement in those with sarcomas, women with clear cell, germ cell, and sex cord stromal tumors did not show an improvement associated with a more extensive lymphadenectomy. Patients with grade 3 disease had an improved survival rate associated with the extent of lymph node resection (74.4%, 87.5%, and 90.5%; P<.001). There was also a nonstatistical improvement in grade 1 or grade 2 disease.
On multivariable analysis, younger age, extent of surgery, lower stage and grade, favorable histologic cell types, and extent of lymphadenectomy remained as significant independent prognostic factors for improved survival. However, race and year of diagnosis (as a continuous variable) were not significant (Table 4).
In 1988, the International Federation of Gynecology and Obstetrics implemented a surgical staging scheme for ovarian cancer that included pelvic and para-aortic lymph node sampling or lymphadenectomy. However, there are limited studies that have shown the benefit of lymphadenectomy in those patients with early-stage disease. In this large population-based study, we evaluated the efficacy of lymphadenectomy in clinical stage I ovarian cancer.
Several mechanisms may explain the improvement in survival associated with lymphadenectomy. With an extensive lymphadenectomy, the surgeon can obtain a sufficient number of nodes to adequately stage patients. Thus, the survival difference observed in this study may simply be due to the comparison of patients with true stage I disease after a thorough staging procedure with inaccurately staged patients with true stage IIIC disease. Prior studies have shown that up to 30% of women who were presumed to have early-stage ovarian cancers are upstaged during their restaging procedures.11–13 Consequently, an adequate staging procedure will guide the physician in providing the most appropriate adjuvant treatment. Furthermore, a thorough lymphadenectomy may improve the patient’s survival by removing micrometastatic disease within the node that was not detected on routine hematoxylin and eosin analyses.20 These findings suggest that clonogenic tumor cells can potentially develop into macrometastatic nodal disease that initially would have been considered negative on pathological examination. Additionally, because of the high probability of developing chemo-resistance during therapy, it is likely that the survival benefit experienced by patients who underwent lymphadenectomy is attributable to the removal of resistant clones of cells and regions of poor blood supply rather than a dramatic reduction in tumor volume.
To estimate whether the extent of lymphadenectomy improves survival, we divided our study group into three different nodal groups to demonstrate the benefits of lymphadenectomy over nodal sampling. Given that the number of nodes resected is merely a surrogate for showing the benefits of lymphadenectomy compared with sampling, it remains to be determined if there exists an absolute number of nodes removed that clearly defines a therapeutic lymphadenectomy. In addition, nodal counts may depend on various factors, such as comprehensiveness of pathologic analysis, surgical expertise, and anatomical variations among patients. Although this current study and many other retrospective studies have demonstrated a survival benefit in those who had a more extensive lymphadenectomy, there are certain patients in whom lymph node sampling or lymphadenectomy may not be considered feasible because of comorbid factors, blood loss, or body habitus. In addition, women under the age of 50 years had no benefit from lymphadenectomy, which may be attributed to the higher percentage of good prognostic cancers such as germ cell tumors and sex cord stromal tumors of the ovary in the younger age group. More specifically, patients under 50 years of age were more likely to present with nonepithelial cancers compared with their older counterparts (9.8% compared with 4.3%). Furthermore, given the excellent outcomes of these patients with lower grade of disease, it is difficult to demonstrate a survival benefit associated with lymphadenectomy in this small subset of younger women with excellent prognosis. In a subset analysis of younger patients with epithelial ovarian cancers, the 5-year disease-specific survival rate of those who had fewer than 10 nodes compared that of those who had 10 or more nodes removed was 93.9% compared with 93.7%; P=.66. Nevertheless, even in patients with clinically apparent early-stage disease, there is a significant risk of nodal metastases.14,21 Cass et al14 found that 15% of patients with clinical stage I disease will have microscopic lymph node metastases. Moreover, when bilateral lymph node sampling was performed, the risks of isolated ipsilateral, contralateral, and bilateral metastases were 50%, 30%, and 20%, respectively.
Our study was limited because of the lack of information on adjuvant chemotherapy, subsequent surgical procedures, surgeon subspecialty, and central pathology review. One of the major limitations of our paper is that we do not have information on adjuvant chemotherapy. It is possible that those patients who underwent an extensive lymphadenectomy may have received more chemotherapy resulting in a better survival. However, the benefit of the extent of lymphadenectomy was evident even in the subgroups of patients with grade 3 disease, with a nonstatistical improvement in grade 1 and 2 tumors. Thus, if we were to assume that all women with grade 3 and clear cell carcinoma received chemotherapy based on recommended guidelines, the survival advantage in those who underwent lymphadenectomy persists. In fact, the benefit was not simply in those with lymph node resection but also in patients who had a more extensive lymphadenectomy (0 nodes compared with fewer than 10 nodes compared with 10 or more nodes).
Moreover, another potential limitation is that we were unable to identify the subspecialty of the surgeons who cared for the patients in our study cohort. In a recent study of 2,150 women with primary epithelial ovarian cancer, Cress et al22 found that up to 20% of young patients with early-stage high risk cancers did not undergo adjuvant chemotherapy, despite scientific evidence and published guidelines that advocate adjuvant chemotherapy. However, women who were treated by a gynecologic oncologist had a greater than two-fold higher chance than other patients to receive chemotherapy. It is possible that subspecialists with adequate surgical training and understanding of the disease process influence the aggressiveness of cancer treatment. Thus, having a surgical oncologist present for adequate staging increases the likelihood that the patients will receive an adequate staging procedure and subsequent adjuvant therapy.23
The strengths of this study include the fact that this is one of the larger studies on stage I ovarian cancer evaluating the effect of lymphadenectomy on survival. However, these conclusions can potentially be misleading if there is an overreliance on interpreting the probability values for each subgroup. Our analytic approach requires that smaller subgroups exhibit a much greater benefit than that experienced by larger cohorts to attain statistical significance. For example, even though we showed a statistically insignificant +11.2% survival improvement in the small subgroup of patients with ovarian sarcomas associated with lymphadenectomy, this finding may still suggest a clinically meaningful improvement because the overall survival of sarcoma patients is so poor.
The wide geographical distribution of patients, including 12 U.S. regions, also decreases the potential selection and surveillance biases that are associated with single-institution analyses. Furthermore, the results from this population-based study can be generalized to the entire U.S. population since the SEER cancer registries are consistent in representative regions throughout the country.24 The SEER program’s quality control measures allow the registry to maintain the highest level of certification of data quality and completeness reported by the Northern American Association of Central Cancer Registries. Part of the quality assurance mechanism includes reviewing the medical records of sample cases on an annual basis for accuracy. Virnig et al25 noted a 98% completeness in each sample case, with a more than 90% rate in the accuracy of reporting adjuvant therapy. The Surveillance, Epidemiology and End Results program was also shown to be reliable in reporting surgical procedures as well.26
Without the explicit ability to prove that an ovarian tumor is benign preoperatively or during surgery, consultation with a physician with advanced training in gynecologic cancer surgery should be considered because our data suggest that women with stage I non–clear cell epithelial ovarian cancers who underwent lymphadenectomy had a significant improvement in survival.
1. Kohler M, Janz I, Wintzer HO, Wagner E, Bauknecht T. The expression of EGF receptors, EGF-like factors and c-myc in ovarian and cervical carcinomas and their potential clinical significance. Anticancer Res 1989;9:1537–47.
2. DiSaia PJ, Creasman WT. Clinical gynecologic oncology. 6th ed. St. Louis (MO): Mosby; 2002.
3. FIGO Cancer Committee. Staging announcements. Gynecol Oncol 1986;25:383–5.
4. Chan AD, Essner R, Wanek LA, Morton DL. Judging the therapeutic value of lymph node dissections for melanoma. J Am Coll Surg 2000;191:16–22; discussion 22–3.
5. Krag DN, Single RM. Breast cancer survival according to number of nodes removed. Ann Surg Oncol 2003;10:1152–9.
6. Weir L, Speers C, D’Yachkova Y, Olivotto IA. Prognostic significance of the number of axillary lymph nodes removed in patients with node-negative breast cancer. J Clin Oncol 2002;20:1793–9.
7. Sosa JA, Diener-West M, Gusev Y, Choti MA, Lange JR, Dooley WC, et al. Association between extent of axillary lymph node dissection and survival in patients with stage I breast cancer. Ann Surg Oncol 1998;5:140–9.
8. Tepper JE, O’Connell MJ, Niedzwiecki D, Hollis D, Compton C, Benson 3rd, AB et al. Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 2001;19:157–63.
9. McGowan L, Lesher LP, Norris HJ, Barnett M. Misstaging of ovarian cancer. Obstet Gynecol 1985;65:568–72.
10. Trimbos JB, Schueler JA, van Lent M, Hermans J, Fleuren GJ. Reasons for incomplete surgical staging in early ovarian carcinoma. Gynecol Oncol 1990;37:374–7.
11. Young RC, Decker DG, Wharton JT, Piver MS, Sindelar WF, Edwards BK, et al. Staging laparotomy in early ovarian cancer. JAMA 1983;250:3072–6.
12. Helewa ME, Krepart GV, Lotocki R. Staging laparotomy in early epithelial ovarian carcinoma. Am J Obstet Gynecol 1986;154:282–6.
13. Soper JT, Johnson P, Johnson V, Berchuck A, Clarke-Pearson DL. Comprehensive restaging laparotomy in women with apparent early ovarian carcinoma. Obstet Gynecol 1992;80:949–53.
14. Cass I, Li AJ, Runowicz CD, Fields AL, Goldberg GL, Leuchter RS, et al. Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas. Gynecol Oncol 2001;80:56–61.
15. Puls LE, Carrasco R, Morrow MS, Blackhurst D. Stage I ovarian carcinoma: specialty-related differences in survival and management. South Med J 1997;90:1097–100.
16. Zanetta G, Rota S, Chiari S, Bonazzi C, Bratina G, Torri V, et al. The accuracy of staging: an important prognostic determinator in stage I ovarian carcinoma. A multivariate analysis. Ann Oncol 1998;9:1097–101.
17. Young RC, Walton LA, Ellenberg SS, Homesley HD, Wilbanks GD, Decker DG, et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med 1990;322:1021–7.
18. Sonoda Y. Management of early ovarian cancer. Oncology (Williston Park) 2004;18:343–56; discussion 358, 361–2.
19. Mandell RB, Mandell LZ, Link CJ Jr. Radioisotope concentrator gene therapy using the sodium/iodide symporter gene. Cancer Res 1999;59:661–8.
20. Girardi F, Petru E, Heydarfadai M, Haas J, Winter R. Pelvic lymphadenectomy in the surgical treatment of endometrial cancer. Gynecol Oncol 1993;49:177–80.
21. Morice P, Joulie F, Camatte S, Atallah D, Rouzier R, Pautier P, et al. Lymph node involvement in epithelial ovarian cancer: analysis of 276 pelvic and paraaortic lymphadenectomies and surgical implications. J Am Coll Surg 2003;197:198–205.
22. Cress RD, O’Malley CD, Leiserowitz GS, Campleman SL. Patterns of chemotherapy use for women with ovarian cancer: a population-based study. J Clin Oncol 2003;21:1530–5.
23. Petignat P, Vajda D, Joris F, Obrist R. Surgical management of epithelial ovarian cancer at community hospitals: a population-based study. J Surg Oncol 2000;75:19–23.
24. Hankey BF, Ries LA, Edwards BK. The surveillance, epidemiology, and end results program: a national resource. Cancer Epidemiol Biomarkers Prev 1999;8:1117–21.
25. Virnig BA, Warren JL, Cooper GS, Klabunde CN, Schussler N, Freeman J. Studying radiation therapy using SEER-Medicare–linked data. Med Care 2002;40 suppl:IV–49–54.
© 2007 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
26. Cooper GS, Virnig B, Klabunde CN, Schussler N, Freeman J, Warren JL. Use of SEER-Medicare data for measuring cancer surgery. Med Care 2002;40 suppl:IV–43–8.