Obstetrics & Gynecology:
Adjuvant Radiotherapy in Incompletely Staged IC and II Endometrioid Uterine Cancer
Parthasarathy, Anand MD, MPH1; Kapp, Daniel S. MD, PhD2; Cheung, Michael K.1; Shin, Jacob Y.1; Osann, Kathryn PhD3; Chan, John K. MD1
From the 1Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, UCSF Comprehensive Cancer Center, San Francisco, California; 2Division of Radiation Therapy, Department of Radiation Oncology, Stanford University School of Medicine, Stanford Cancer Center, Stanford, California; and 3Division of Hematology and Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, California.
Corresponding author: John K. Chan, MD, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, UCSF Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143-1702; e-mail: email@example.com.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
OBJECTIVES: To estimate if adjuvant radiotherapy improves the disease-specific survival of patients with clinical stage IC and II endometrioid corpus cancer who did not undergo lymphadenectomy.
METHODS: Information was obtained on patients with endometrioid corpus cancer from the National Cancer Institute database between 1988 and 2001. Data were analyzed using Kaplan-Meier and Cox proportional hazards regression methods.
RESULTS: A total of 3,664 patients (median age 70 years) with clinical stage IC to II endometrioid carcinoma did not undergo lymphadenectomy, of which 2,170 had stage IC and 1,494 stage II disease. Of these, 1,175 had grade 1, 1,637 had grade 2, 693 had grade 3, and in 159, grade was unknown. The 5-year disease-specific survival rates of clinical stage IC compared with stage II patients were 91.3% and 86.7% (P<.001). Of the 1,964 who received adjuvant radiotherapy, the 5-year disease-specific survival rate was 89.9% compared with 87.8% in those who did not undergo further treatment (P=.04). Adjuvant radiation improved the disease-specific survival rate of those with stage II disease, (86.5% compared with 81.9%; P=.02), but not in those with stage IC disease (91.7% compared with 92.6%; P=.68). The benefit of radiotherapy was significant in patients with grade 3 disease and patients 70 years or older (88.2% compared with 83.3%; P<.001). On multivariable analysis, age, stage, and grade were significant independent prognostic factors for disease-specific survival.
CONCLUSION: Adjuvant radiotherapy marginally improved the survival of clinically staged IC-II endometrioid uterine cancer patients without lymphadenectomy. After excluding those without hysterectomy, radiotherapy did not significantly affect disease-specific survival.
LEVEL OF EVIDENCE: II
Cancers of the uterus are the most common gynecologic malignancy, accounting for a projected 39,080 cases in the United States in 2007, with 7,400 associated deaths.1,2 The vast majority are tumors of the endometrium, primarily adenocarcinomas. Known risk factors for endometrial cancer include older age, obesity, endogenous estrogen, and tamoxifen use.3–10
Endometrial cancers are staged surgically, and the vast majority of cases are stage I, or confined to the endometrium and/or myometrium. Complete surgical staging includes a hysterectomy, bilateral salpingo-oophorectomy, pelvic and paraaortic lymph node dissection, and peritoneal fluid/washing collection.11,12 Although lymph node dissection is important for surgical staging, this may not be accomplished in all cases. Factors that may preclude lymph node dissection include patient's body habitus, medical morbidity, lack of surgical expertise, and incidental finding of uterine cancer after surgery for presumed benign disease. Although the results of the A Study in the Treatment of Endometrial Cancer (ASTEC) trial showed that pelvic lymphadenectomy did not provide a survival benefit, the value of lymphadenectomy is difficult to demonstrate, given the overall favorable outcome of these women with low-risk uterine cancer (Kitchener H, Redman C, Swart A, Amos CL. ASTEC—A study in the treatment of endometrial cancer: randomized trial of lymphadenectomy in the treatment of endometrial cancer [abstract]. Gynecol Oncol 2006;101:S21–S2).
The role of radiation therapy in the postoperative setting in endometrial cancer is controversial. Two relatively recent, prospective, randomized trials examined the use of external radiation therapy in the postoperative setting.13,14 In the Gynecologic Oncology Group (GOG) 99 study, which included lymphadenectomy, patients with stages IB, IC, or II (occult) disease were randomly assigned to no further treatment or 50.4 Gy pelvic radiotherapy. In the Postoperative Radiotherapy in Endometrial Carcinoma Trial, no lymphadenectomy was performed, and patients with stage IB (grade 2 or 3) and stage IC (grade 1 or 2) were randomly assigned to no further treatment or 46 Gy pelvic therapy. Of note, patients with stage IA (all grades) and IC (grade 3) were excluded. Although the patient and treatment characteristics were different, both trials demonstrated that postoperative radiation decreased local-regional recurrences without an improvement in survival. A prior study analyzing stage IC patients with all histologic cell types after surgical staging found an improved survival associated with adjuvant radiotherapy.15 However, there were no reports including large numbers of patients that evaluated the benefit of radiation therapy in patients with stage IC and II endometrioid uterine cancer who did not undergo lymphadenectomy. In this current report, we compare the survival rates of patients with clinical stage IC and II endometrioid uterine cancer, treated with or without adjuvant radiation therapy.
PATIENTS AND METHODS
Demographic, clinicopathologic, treatment, and survival information for women diagnosed with endometrioid corpus cancer during the period from January 1, 1988, through December 31, 2001, were obtained from the Surveillance, Epidemiology and End Results (SEER) database of the United States National Cancer Institute. This database is representative of approximately 14% of the U.S. population and is reported from 12 population-based registries, including San Francisco–Oakland, Connecticut, metropolitan Detroit, Hawaii, Iowa, New Mexico, Seattle (Puget Sound), Utah, metropolitan Atlanta, Alaska, San Jose–Monterey, and Los Angeles.16
Of 47,341 patients who were diagnosed with endometrial cancer, we excluded 3,131 with uterine papillary serous carcinoma, 716 with clear cell carcinoma, 4,067 with sarcomas, and 31 with other rare histologic cell types. Of the remaining 39,396 women with endometrioid corpus cancer, 6,632 had stage IC or II disease. The 3,664 of these patients who did not undergo a lymphadenectomy (defined as removal of at least one lymph node) comprise our study population. An additional analysis was performed after excluding those who did not undergo a hysterectomy. Radiation treatment was defined as those who received external beam radiation and/or vaginal brachytherapy.
To better characterize our patient population, the race classifications of the SEER program were categorized into four groups: whites, African Americans, Asians, and others. Asians were arbitrarily defined as Chinese, Japanese, Korean, Vietnamese, and Filipina. All other race and ethnicity classifications were defined as “others.”
Statistical analysis was performed using the Intercooled Stata 8.0 program (StataCorp LP, College Station, TX). Demographic, clinical, histologic, and treatment characteristics were compared using the χ2 test. Means were compared using a two-sample t test assuming unequal variances. Survival analysis was performed using the Kaplan-Meier estimates of survival probability, and the Cox proportional hazards model was used to identify independent predictors of survival. The outcome of interest was death from uterine cancer, and time to death was censored in women who died of causes other than uterine cancer. All characteristics that were tested in univariate analysis were included in the multivariate model. A two-tailed P<.05 was considered statistically significant. This study was reviewed and approved by the Institutional Review Board.
A total of 3,664 women with clinical stage IC or II endometrioid carcinoma did not undergo lymphadenectomy, of which 2,170 (59%) had clinical stage IC and 1,494 (41%) had stage II disease. The median age was 70 years (range 25–102 years). Of these, 3,158 (86%) patients were white, 184 (5%) were Hispanic, 140 (4%) were African American, 122 (3%) were Asian, and 60 (2%) patients were other. A total of 1,175 had grade 1, 1,637 had grade 2, 693 had grade 3, and 159 were unknown. One thousand nine hundred sixty-four (54%) women underwent radiotherapy, and 1,700 (46%) received no radiation treatment.
Patient demographics and clinicopathologic information are shown on Table 1. Patients who received adjuvant radiotherapy were significantly younger than those who did not, with a median age of 69 years compared with 73 years. Additionally, a significantly higher proportion of white patients received adjuvant radiotherapy compared with others (54.4% compared with 45.6%; P<.001). The proportion of women with grade 1 disease who underwent radiotherapy was significantly lower than those with grade 2–3 disease (49.2% compared with 56.7%; P<.001).
The 5-year disease-specific survival rates of women who did and did not undergo adjuvant radiotherapy are shown on Table 2. Overall, women who received radiotherapy had a survival advantage compared with those who had no adjuvant radiation treatment (89.9% compared with 87.8%; P=.04; Fig. 1). When stratified by age, women aged 70 years or older who received radiotherapy had a survival advantage over those who did not (88.2% compared with 83.3%; P<.001). However, radiotherapy did not seem to benefit those aged younger than 70 years (91.4% compared with 93.6%; P=.08). The 5-year disease-specific survival rate of clinical stage IC compared with stage II patients was 91.3% compared with 86.7% (P<.001). More specifically, adjuvant radiation improved the outcome of those with stage II disease (86.5% compared with 81.9%; P=.02) but not those with stage IC disease (91.7% compared with 92.6%; P=.68). On analysis stratified by grade, radiotherapy benefited women with grade 3 disease (75.5% compared with 67.4%; P=.003). For grades 1 (96.4% compared with 95.5%; P=.42) and 2 (91.9% compared with 88.5%; P=.06), radiotherapy was associated with a slight survival advantage, but this difference was not statistically significant (Fig. 2).
A subset analysis was performed that included only patients who underwent a hysterectomy. One hundred thirty-two patients who did not have a hysterectomy were excluded from this analysis; none of these women received radiation. In univariate analysis, adjuvant radiation did not improve the disease-specific survival rate in this subgroup of patients. In a further analysis on the causes of death, our data showed that of the 1,265 patient who died; 901 (71.2%) died of other causes. Alternatively, only 28.8% of patients died of endometrial cancer.
On multivariable analysis, younger age, earlier stage, and lower grade were significant independent prognostic factors for survival (Table 3). However, race and year at diagnosis were not important prognosticators.
Current recommendations for the use of postoperative radiation in lymph node negative patients continue to be controversial. Even though the 5-year overall survival rate of women with stage I disease who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy and adjuvant radiation ranges from 80% to 90%, there are subgroups of patients with stage IC and II disease who have poorer outcomes, with increase risk for both local and distant recurrence.13 Two relatively recent, prospective, randomized trials examined the use of external radiation therapy in the postoperative setting and found that adjuvant radiation decreased local recurrences without an improvement in survival.13,14 Previously, Aalders et al17 reported a phase III trial on patients with stage I endometrial cancer to evaluate the benefit of adjuvant external beam radiation after surgery and vaginal brachytherapy. Although they were unable to identify a survival improvement in the overall study group, these authors did note a survival advantage in those with grade 3 and stage IC disease from 18% to 27%. A recent population-based study analyzing stage IC patients after clinical and surgical staging found an improved survival associated with adjuvant radiotherapy.15 However, this analysis did not specifically evaluate patients who did not undergo lymph node dissection or those with stage II disease. Moreover, they included patients with all histologies, including high-risk subtypes. To expand on these prior studies, we analyzed the outcomes of women with stage IC-II endometrioid uterine cancer who did not undergo lymph node dissection to determine the potential benefit of adjuvant radiotherapy.
In this large population-based analysis of 3,664 women, our results showed a marginal disease-specific survival benefit for the use of postoperative radiation treatment. Although this benefit was relatively small in the overall study group, the benefit was greater (approximately 5% increase in 5-year disease-specific survival) in higher-risk subgroups, including the elderly (aged 70 years or older), those with grade 3 disease, and those with stage II disease. These findings reflect those of prior randomized clinical trials. Particularly, the GOG protocol 99 trial also found a progression-free survival benefit in the high-intermediate risk group defined as those 1) with moderate to poorly differentiated tumor, presence of lymphovascular invasion, and outer third myometrial invasion; 2) aged 50 years or older with any two risk factors listed above; or 3) aged at least 70 years with any additional risk factor. However, an overall survival benefit was not evident in these clinical trials. This may be attributed to the limitations of the sample size, limited follow-up, or development of distant metastases in high-risk patients, and death due to other causes limiting the number of patients available for long-term follow-up.
The patients who did not have a hysterectomy had a poorer outcome with a 5-year disease-specific survival rate of only 45%. The authors hypothesize that the poorer survival of this group of patients may have adversely affected the survival of those who did not receive radiotherapy. However, these patients without hysterectomy had a significantly shorter follow-up at only 26.0 months compared with 64.9 months in the group that underwent a hysterectomy (P<.001). Furthermore, none of these patients received radiation therapy, and they had a poor prognosis. The clinician needs to take these data into account in the management of these patients. Our subset analysis also showed that only 28.8% of patients died from endometrial cancer in this large population-based study. Clearly, it would be difficult to show a disease-specific survival benefit associated with adjuvant radiotherapy given that more than 70% of the study population died of other causes.
Multiple studies are emerging showing the benefit of complete node dissection in endometrial cancer.18–20 Alternatively, data from the ASTEC trial has not shown a survival benefit with lymphadenectomy (Kitchener H et al. ASTEC—A study in the treatment of endometrial cancer: randomized trial of lymphadenectomy in the treatment of endometrial cancer [abstract]. Gynecol Oncol 2006;101:S21–S2). However, there are clinical situations where patients may not have received a lymph node assessment. This current study showed that such patients can benefit from additional adjuvant radiotherapy, in particular those with grade 3 or clinical stage II disease. The Dutch Post Operative Radiation Therapy in Endometrial Carcinoma study comprised a group similar to ours who did not receive a node dissection. Although this study showed a decrease of about 10% in local recurrence associated with the use of postoperative radiation treatment, they were unable to identify a benefit in overall survival. More recently, there have been reports of radiation combined with chemotherapy demonstrating a survival advantage associated with adjuvant therapy in high-risk patients with stage IC to IIIA disease (Hogberg T, Rosenberg P, Kristensen G, de Oliveira CF, de Pont Christensen R, Sorbe B, et al. A randomized phase-III study on adjuvant treatment with radiation [RT] ± chemotherapy [CT] in early-stage high-risk endometrial cancer [abstract]. J Clin Oncol 2007;25 suppl:5503). Clearly, the specific role of adjuvant treatment in high-risk endometrioid uterine cancer warrants further investigation. The results from the ASTEC trial after random assignment of patients to radiotherapy compared with no further treatment can further elucidate the role of adjuvant radiotherapy in these high-risk patients (Kitchener H et al. ASTEC—A study in the treatment of endometrial cancer: randomized trial of lymphadenectomy in the treatment of endometrial cancer [abstract]. Gynecol Oncol 2006;101:S21–S2).
Our study was limited by the lack of information on surgeon specialty, extent of residual disease, adjuvant hormonal and chemotherapy, time to recurrence, patient performance status, subsequent surgical and medical therapies, and surgical morbidity. With respect to chemotherapy, given that there are no published studies that have shown a survival benefit in the use of chemotherapy for stage I-II disease, we doubt that chemotherapy was administered in these early-stage (I-II) patients and that its use would bias our results. However, the results of GOG-122 should be noted: women with stage III or IV disease had improved survival with chemotherapy (cisplatin and doxorubicin) compared with abdominopelvic radiation.21 Furthermore, there was no information on the reason for lack of node sampling. For example, a case in which the surgeon encounters a large, obviously positive lymph node and decides to forsake dissection is much different from a case in which lymph nodes are not examined. In addition, patients with severe medical comorbidities may have had less extensive surgery, and this, rather than any treatment characteristics, may explain their poor outcome. Second, the SEER database omits key information on radiation therapy, such as dose, field arrangement, and fractionation. Nonetheless, with this in mind and based on patterns of referral, we would expect the group that received radiation to have worse prognostic factors. This would negate any of the confounding problems mentioned. As with other large population-based studies, our report was limited by a lack of central pathology review. To determine whether there are significant discrepancies between registry and referral pathologists, Tyler et al22 performed slide reviews on 477 women diagnosed with ovarian, breast, or endometrial cancer and compared the diagnoses of pathologists contributing to tumor registries affiliated with the SEER program to an expert panel of three gynecologic pathologists. They found an overall agreement of 97% for overall cancers, and the agreement for major cellular subtypes of ovarian cancer was 73% for endometrioid and 100% for clear cell carcinomas. Moreover, there was a 61.7% complete histopathologic agreement with only 1% of cases that were considered as having major differences.
The data from this population-based study allow one to generate interesting hypotheses. The strength in the large number of patients in this study may overcome potential limitations, such as biases associated with large population-based analyses. Additionally this current study is one of the largest series to date of unselected patients encompassing 12 regions in the United States. As such, this cohort of patients is not limited by the selection and surveillance biases often associated with clinical trials and studies from single academic institutions. In addition, the demographic and clinicopathologic data obtained from this report are a close reflection of the trends and outcomes of U.S. women diagnosed with endometrioid uterine carcinoma who receive medical care from community hospitals based on diagnoses from contributing pathologists rather than from academic gynecologic pathologists.23 The SEER program's quality control maintains a high level quality and complete data certification reported by the Northern American Association of Central Cancer Registries.24 More specifically, the quality assurance program includes an annual review of the medical records of sample cases for accuracy. Virnig et al reported a 98% completeness in each sample case with a more than 90% rate in the accuracy of reporting adjuvant radiation therapy.25
The management of a patient with clinical stage IC or II endometrioid cancer is complex and needs to consider whether the patient had a hysterectomy, the risks and benefits of performing a complete lymphadenectomy, the side effects of radiation therapy, and the likelihood and consequences of local–regional failure. Therefore, treatment with radiotherapy needs to be individualized. There are significant associated comorbidities in these patients. In fact, more than 70% of the patients in our study died of causes other than endometrial cancer. In the overall study group, aged 70 years or older, stage II disease, and grade 3 tumors benefited from adjuvant radiotherapy. However, when patients who did not undergo hysterectomy were excluded from our analysis, no significant improvement of disease-specific survival was associated with adjuvant radiotherapy, which is in agreement with a recent randomized trial.13
2. Jemal A, Siegel R, Ward E, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.
3. Soliman PT, Oh JC, Schmeler KM, Sun CC, Slomovitz BM, Gershenson DM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol 2005;105:575–80.
4. Gredmark T, Kvint S, Havel G, Mattsson LA. Adipose tissue distribution in postmenopausal women with adenomatous hyperplasia of the endometrium. Gynecol Oncol 1999;72:138–42.
5. Folsom AR, Kaye SA, Potter JD, Prineas RJ. Association of incident carcinoma of the endometrium with body weight and fat distribution in older women: early findings of the Iowa Women's Health Study. Cancer Res 1989;49:6828–31.
6. Siiteri PK. Adipose tissue as a source of hormones. Am J Clin Nutr 1987;45:277–82.
7. Zeleniuch-Jacquotte A, Akhmedkhanov A, Kato I, Koenig KL, Shore RE, Kim MY, et al. Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study. Br J Cancer 2001;84:975–981.
8. Lukanova A, Lundin E, Micheli A, Arslan A, Ferrari P, Rinaldi S, et al. Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women. Int J Cancer 2004;108:425–32.
9. Nyholm HC, Nielsen AL, Lyndrup J, Dreisler A, Hagen C, Haug E. Plasma oestrogens in postmenopausal women with endometrial cancer. Br J Obstet Gynaecol 1993;100:1115–9.
10. Cohen I. Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol 2004;94:256–66.
13. Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, 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;355:1404–11.
14. Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, 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 [published erratum appears in Gynecol Oncol 2004;94:241–2]. Gynecol Oncol 2004;92:744–51.
15. Lee CM, Szabo A, Shrieve DC, Macdonald Gaffney DK. Frequency and effect of adjuvant radiation therapy among women with stage I endometrial adenocarcinoma [published erratum appears in JAMA. 2006;295:2482]. JAMA 2006;295:389–97.
16. U.S. Department of Health and Human Services—National Cancer Institute, (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 9 Regs Public-Use, Nov 2004 Sub (1973–2001): National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch. Bethesda (MD): National Cancer Institute, Cancer Statistics Branch; 2004.
17. Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980;56:419–27.
18. Chan JK, Cheung MK, Huh WK, Osann K, Husain A, Teng NN, et al. Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients. Cancer 2006;107:1823–30.
19. Havrilesky LJ, Cragun JM, Calingaert B, Synan I, Secord AA, Soper JT, et al. Resection of lymph node metastases influences survival in stage IIIC endometrial cancer. Gynecol Oncol 2005;99:689–95.
20. Trimble EL, Kosary C, Park RC. Lymph node sampling and survival in endometrial cancer. Gynecol Oncol 1988;71:340–3.
21. Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J. Ramdomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 2006;24:36–44.
22. Tyler CW Jr, Lee NC, Robboy SJ, Kurman RJ, Paris AL, Wingo PA, et al. The diagnosis of ovarian cancer by pathologists: how often do diagnoses by contributing pathologists agree with a panel of gynecologic pathologists? Am J Obstet Gynecol 1991;164:65–70.
23. Hankey BF, Ries LA, Edwards BK. The surveillance, epidemiology, and end results program: a national resource. Cancer Epidemiol Biomarkers Prev 1999;8:1117–21.
24. North American Association of Central Cancer Registries. Available at: http://www.naaccr.org/
. Retrieved October 1, 2007.
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 The American College of Obstetricians and Gynecologists