Complete surgical staging of early endometrial adenocarcinoma: Optimizing patient outcomes

Complete Surgical Staging of Early Endometrial Adenocarcinoma: Optimizing Patient Outcomes Mack N. Barnes and Larry C. Kilgore Endometrial adenocarcinoma is the most common gynecologic malignancy. Strategies for treatment of this disease should not only emphasize quality of care resulting in cure of disease, but also use health care resources in the most efficient manner possible. Based on available data, we recommend that all patients with the diagnosis of endometrial carcinoma undergo complete surgical staging with lymph node dissection.

Radiation therapy is reserved only for patients with evidence of extrauterine disease. This approach maximizes the amount of information available for treatment planning and offers the potential therapeutic advantage of lymph node dissection. Additionally, in a cost analysis, this approach appears to be the most cost-effective. Copyright 9 2000 by W.B. Saunders Company

A

potentially toxic and costly adjuvant therapies. Before 1988, endometrial carcinoma was a clinically staged disease. The report by Creasman et al, 2 however, showed that 22% of clinical stage I patients have disease outside the uterus when a comprehensive staging procedure is performed. As a result, the International Federation of Gynecology and Obstetrics mandated that this disease be surgically staged. 3 The procedures required for surgical staging include exploratory laparotomy, washings for cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and an assessment of pelvic and para-aortic lymph nodes. The requirement for assessment of lymph nodes has been the subject of considerable debate. Lymph node assessment within the context of staging endometrial carcinoma appears to be reasonable given the 10% incidence of nodal metastases. This rate of detection is similar to other surgically staged gynecologic malignancies. 4-6 To different practitioners, this assessment may imply imaging, observation, palpation, sampling, or dissection. Data exist, however, that suggest dissection of a meaningful number of lymph nodes is required to detect metastases. As shown by Girardi et al, 7 37% of lymph node metastases are less than 2 mm, whereas ahnost 50% are less than 1 cm. These findings are consistent with those of Creasman et al,2 from the Gynecologic Oncology Group (GOG) surgical staging study of 621 patients, in which fewer than 10% of patients with nodal metastases had grossly positive nodes. Imaging techniques, visualization, and palpation are inadequate to exclude lymph node involvement confidently. The literature suggests there is a subgroup of patients with well-differentiated tumors and limited myometrial invasion with a negligible risk of lymph node metastases. In the GOG data presented by Creasman et al 2 that examined surgical pathological

denocarcinoma of the uterine corpus is the most common malignancy of the female genital tract. An estimated 36,000 new cases occurred in 1998, resulting in 6,300 deaths attributable to this disease.l Because this is a relatively common diagnosis in the postmenopausal woman, strategies for treatment of this disease must not only emphasize quality of care resulting in cure of disease, but also use health care resources in the most efficient manner possible. We present an evidence-based strategy for the treatment of endometrial adenocarcinoma that emphasizes complete surgical staging incorporating lymph node dissection, with radiation therapy reserved for cases in which disease is detected outside the uterine fundus. We believe the literature supports this strategy as the most comprehensive, yet cost-effective approach to the management of this disease. As such, the rationale for this approach to the management of endometrial adenocarcinoma is presented herein.

Endometrial Carcinoma Is a Surgically Staged Disease The staging of cancers has been a critical portion of any consultation performed by an oncologist. Cancer staging systems may yield prognostic information, allow patients to be grouped for research purposes, direct treatment planning, and identify patients with a good prognosis who would derive no benefit from From the Department of Obstetrics and Gynecology,Division of Gynecologic Oncology, The University of Alabama at Birmingham, Birmingham, AL. Address reprint requests"to Mack A( Barnes, MD, Division of Gynecologic Oncology, University of Alabama at Birmingham, 538 Old Ifilbnan Building, 618 South 20th Street, Birmingham, AL 35233- 7333. Copyright 9 2000 by HdB. Saunders Company 1053-4296/00/1001-0001510.00/0

Seminars in Radiation Oncology, Vo110, No 1 (Janua~), 2000."pp 3-7

3

4

Barnes and Kilgore

spread patterns of endometrial cancer, well-differentiated tumors with no or superficial invasion had a risk of lymph node metastases of 0 to 3%. Preoperative identification of this group of patients would preclude lymph node dissection. To date, studies assessing the reliability of biopsy correlates to final pathology, frozen section, and preoperative imaging have yielded inaccuracy rates that preclude their use to eliminate lymph node dissection, aq2 At the University of Alabama at Birmingham, all patients with a biopsy specimen showing endometrial adenocarcinoma undergo complete surgical staging, including dissection of lymph nodes. Dissection of the para-aortic lymph nodes occurs from the bifurcation of the aorta to a point distal to the inferior mesenteric artery. The pelvic lymph node dissection is performed from the bifurcation of the common iliac artery to the circumflex vein, including the obturator nodes above the level of the obturator nerve. The dissection of lymph nodes as part of a staging procedure should produce minimal additional morbidity. Numerous authors have been unable to document increased blood loss, increased transfusion rate, increased hospital stay, or increased complication rate when lymph node dissection is performed in addition to hysterectomy with removal of adnexal structures. 13-15 The performance of surgical staging has had a dramatic influence on survival statistics when compared with a clinical staging system. Accurately staged patients with stage I corpus cancer can anticipate a greater than 90% 5-year survival. 16 Far from being merely a statistical shift, the importance of this finding lies in the accurate identification of a subgroup of patients that would survive without the addition of any adjuvant therapy.

Incorporation of Lymph Node Dissection into the Management of Patients With Endometrial Adenocarcinoma May Improve Survival The removal of regional lymph nodes remains a cardinal principle in the surgical management of most cancers today. 17From a prognostic standpoint, histological documentation of metastases to lymph nodes is associated with a 58% 5-year survival. 18 Several authors have hypothesized that removal of regional lymph nodes (ie, known routes of spread) could potentially influence smwival. An improved outcome in completely surgically staged patients was suggested by Orr et aP 6 in a

retrospective series of 444 patients who underwent total abdominal hysterectomy, bilateral salpingooophorectomy, and peMc and para-aortic lymph node dissection for stage I corpus cancer. Vaginal brachytherapy was administered for grade 2 and 3 or when invasion was documented. No teletherapy was used when disease was confined to the uterus. An overall 5-year survival rate of 97% was obtained, including 97% and 93% survival for stage IB and IC. The long-term outcome of therapeutic pelvic lymphadenectomy for stage I endometrial adenocarcinoma was reported by Mohan et al. m In this retrospective case series, 192 patients with pathological stage I cancer were identified. All patients underwent total abdominal hysterectomy, bilateral salpingooophorectomy, pelvic lymph node dissection, and vaginal brachytherapy. The 15-year overall survival rate was 98%, with recurrences identified in 4% of patients. Grade and depth of invasion were not significant predictors of survival after full pelvic lymph node dissection. The most compelling evidence, to date, for a therapeutic benefit to lymph node dissection is offered by Kilgore et a137 These authors reported a retrospective series of patients undergoing multiplesite lymph node dissection compared with a group of patients who underwent limited or no lymph node sampling. For additional comparison, patients were divided into a low-risk group, in which disease appeared to be confined to the uterus, and a high-risk group, in which disease was detected outside the uterine corpus. Analysis revealed a significantly improved survival when multiple-site lymph node dissection was performed when compared with no lymph node sampling. Smwival was also significantly improved in the low-risk group, compared with the high risk group, with or without radiation therapy and for poorly differentiated tumors when multiple-site lymph nodes were sampled. Although the limitations of a retrospective series were acknowledged, the authors concluded that the survival data from this series indicated improved smwival in patients undergoing multiple-site lymph node sampling. Webb et aF ~ showed a significant improvement in overall survival for patients with para-aortic metastases who underwent para-aortic lymphadenectomy when compared with patients undergoing a sampling procedure (<5 lymph nodes obtained). In addition, Cox regression models suggested that submission to para-aortic lymphadenectomy was a predictor of progression-free survival and overall survival. Evidence that pelvic and para-aortic lymphadenec-

CompleteStagingofEndometrialCarcinoma

tomy improves smwival in another disease context was obtained by Onda et al2a in ovarian adenocarcinoma. In this retrospective study, the authors demonstrated that patients with ovarian carcinoma upstaged to stage Ill after systemic lymphadenectomy have similar survival to stage I-II patients and superior survival to other stage III patients. Although it is tempting to speculate that lymphadenectomy improves survival, the limitations of retrospective reports are recognized. A prospective cooperative group trial to establish the efficacy of therapeutic lymphadenectomy is eagerly awaited.

Proper Identification of Patients at Low Risk for Recurrence Allows for

Elimination of Adjuvant Radiotherapy In addition to yielding prognostic information, accurate surgical staging of endometrial adenocarcinoma allows the oncologist to reserve further therapy for those for whom the literature has revealed a demonstrable benefit. This approach has been met with general acceptance in the treatment of early-stage ovarian and cmvical carcinomas. Specifically, in regard to therapy in early-stage endometrial cancer, the debate has centered on adjuvant radiation tbr patients with stage I disease and high-risk factors for recurrence. These high-risk factors have been considered to be moderately to poorly differentiated tumors, myometrial invasion, aggressive cell types, cervical involvement, and lesion size. Although it is clear from both retrospective and prospective reports that local pelvic control is improved with the addition of radiotherapy, it is doubtful whether or not any survival advantage is obtained. 4 It has been difficult to identify a consistent rationale guiding the use of adjuvant radiation. As illustrated by Morrow et al, 18 49% of patients with endometrial adenocarcinoma and negative risk factors for recurrence received radiation therapy. This series included 14% of patients with grade 1 tumors and no evidence ofmyometrial invasion that received adjuvant radiation. Prospective trials examining the utility of adjuvant radiation therapy in early-stage disease have been unable to document improved survival. In 1980, Aalders et aF 2published a report on a randomized prospective trial of primary surgery and vaginal brachytherapy with and without additional external-beam radiation in patients with endometrial cancer clinically confined to the uterus. As expected, a significant reduction in vaginal and pelvic recurrences was observed in the group receiving

5

adjuvant radiotherapy (1.9% versus 6.9%). More distant recurrences were observed in the treatment group. As a result, the overall 5-year smMval rate was not improved by the institution of external-beam radiation. In a second prospective randomized trial, GOG study #99, patients with endometrial adenocarcinoma unde~vent complete surgical staging with pelvic and para-aortic lymph node dissection23 Patients with intermediate-risk surgical stage I disease were then randomized to no further therapy or 5,040 cGy pelvic radiotherapy. Similar to the observations of Aalders et a122 no significant survival advantage was demonstrated with the use of adjuvant external radiotherapy in surgical stage I patients. Important components of this trial, as it relates to the management of endometrial adenocarcinoma, were the elimination of vaginal brachytherapy and complete surgical staging of all patients. If adjuvant radiotherapy is instituted in an attempt to reduce pelvic recurrence, a relevant question is whether all patients at risk should be treated or therapy should be reserved for patients who experience recurrence. This issue has been addressed by Ackerman et al. 24 These authors showed that 47% to 79% of patients with pelvic recurrence can be adequately controlled when therapy is instituted at the time of relapse. Additionally, when examining the theoretical benefit of irradiating 100 stage I patients, it was noted an excess of only three patients with uncontrolled pelvic disease would be observed if therapy were reserved for recurrence.

Treatment of Early-Stage Endometrial Cancer Should Be Pursued in the Most Cost-Effective Manner Possible Management options in the treatment of early-stage endometrial adenocarcinoma have included surgery, use of frozen sections to guide extent of surgical staging, use of surgical consultants to perform lymph node dissection, and use of adjuvant brachytherapy and teletherapy. Given that several combinations of treatment approaches yield equivalent 5-year survival rates, we have examined the costs of different treatment algorithms using accumulated hospital charges as an end point25 Three clinical algorithms for the treatment of endometrial adenocarcinoma were considered: (1) comprehensive surgical staging with lymph node dissection and external-beam radiation reserved for patients with documented extrauterine disease; (2) total abdominal hysterectomy with

6

Barnes andKilgore

bilateral salpingo-oophoretomy on all patients, lymph node dissection when uterine invasion documented, no radiation therapy for Stage IA, grade 1 disease, vaginal brachytherapy for stage IB, grade 2, and adjuvant external radiotherapy for all other cases (consistent with clinical guidelines proposed by Society of Gynecologic Oncologists)26; and (3) similar to algorithm 2, however, a frozen section was obtained and the lymph node dissection was performed by a surgical consultant. Each algorithm was applied to a cohort of 190 surgically staged patients identified through a retrospective chart review. T r e a t m e n t algorithm 1 yielded the lowest cost per patient, at $12,778.52. T r e a t m e n t algorithms 2 and 3 had associated costs per patient of $15,997.02 and $17,343,44. The impact of the differences in charges per patient is realized when these figures are applied to the estimated 36,100 new cases of endometrial cancer that occurred in 1998.1 Based on hospital charges (which are greater than payments) used in our study, one can anticipate an additional national expenditure of $115,866,450 when the Society of Gynecologic Oncologists clinical guidelines are employed and $164,337,570 when frozen section diagnoses are obtained and surgical consultants are used. These findings are consistent with other authors who have suggested potential cost savings when adjuvant radiotherapy for early-stage disease is eliminated. O r r et all6 reviewed 444 patients with stage I endometrial cancer who underwent comprehensive surgical staging followed by vaginal brachytherapy. These authors noted that an additional $3.8 million in charges would have resulted if adjuvant radiotherapy had been employed in this patient population. Fanning and Firestein 27 reported a cost saving of 39% for t r e a t m e n t of early-stage endometrial cancer with lymphadenectomy and vaginal brachytherapy compared with selective lymphadenectomy and teletherapy.

Conclusions We propose a m a n a g e m e n t scheme whereby all patients with biopsy-proven endometrial adenocarcin o m a undergo complete surgical staging as mand a t e d by The International Federation of Gynecology and Obstetrics. A critical component of this managem e n t scheme is the performance of a pelvic and para-aortic lymph node dissection. This portion of the staging procedure allows the accurate identification of patients who would realize no added survival benefit from the addition of costly adjuvant radiation

therapy. The potential survival benefit realized with the inclusion of lymph node dissection is exciting but awaits more stringent testing in prospectively designed trials.

References 1. Landis S, Murray T, Bolden S, et al: Cancer statistics, 1998. CancerJ Clin 48:6=30, 1998 2. Creasman W, Morrow C, Bundy B, et al: Surgical pathologic spread patterns of endometrial cancer: A GynecologicOncology Group study.Cancer 60:2035-2041, 1988 3. International Federation of Gynecologyand Obstetrics: Annual report on the results of treatment in gynecologiccancer. IntJ GynecolObstet 28:189-190, 1989 4. Barakat R, Park R, GrigsbyP, et al: Corpus: Epithelial tumors, in HoskinsW, Perez C, YoungR (eds): Principlesand Practice of GynecologicOncology.Philadelphia, PA, Lippincott-Raven, 1997 5. Stehman F, Perez C, Kurman R, et al: Uterine cervix, in HoskinsW, Perez C, Young R (eds): Principles and Practice of Gynecologic Oncology. Philadelphia, PA, Lippincott-Raven, 1997. 6. Ozols R, Rubin S, Thomas G, et al: Epithelial ovarian cancer, in HoskinsW, Perez C, Young R (eds): Prin@es and Practice of GynecologicOncology.Philadelphia, PA, Lippincott-Raven, 1997 7. Girardi F, Petru E, Heydarfadi M, et al: Pelviclymphadenectomy in the surgicaltreatment of endometrial cancer. Gynecol Onco149:177-180, 1993 8. Larson D,Johnson K, Broste S, et al: Comparison of D&C and office endometrial biopsy in predicting final histopathologic grade in endometrial cancer. Obstet Gyneco186:38-42,1995 9. Shim J, Rose P, Reale F, et al: Accuracy of frozen section diagnosis at surgery in clinical stage I and II endometrial carcinoma.AmJ Obstet Gynecol 166:1335-1338, 1992 10. Zorlu C, Kuscu E, Ergun Y, et al: Intraoperative evaluation of prognostic factors in stage I endometrial cancer by frozen section:How reliable?Acta Obstet GynecolScand 72:382-385, 1993 11. Sironi S, Taccagni G, Garancini P, et aI: Myometrial invasion by endometrial carcinoma:Assessment by MR imaging. AmJ Radio1158:565-569, 1992 i2. DelMaschio A, Vanzulli A, Sironi S, et al: Estimating the depth of myometrial involvementby endometrial carcinoma: Efficacy of transvaginal sonography vs MR imaging. Am j Radio1160:533-538, 1993 13. Larson D,Johnson K: Pelvicand paraaortic lymphadenectomy for surgicaistaging of high risk endometrioid adenocarcinoma of the endometrium. GynecolOncol 51:345-348, 1993 14. Homesley H, Kadar N, Barrett R, et al: Selectivepelvic and periaortic lymphadenectomy does not increase morbidity in surgical staging of endometrial carcinoma. Am J Obstet Gyneco1167:1225-1230, 1992 15. Moore D, FowlerW, Walton L, et al: Morbidityof lymph node sampling in cancers of the uterine corpus and cer~x. Obstet Gyneco174:180-184, 1989 16. OrrJ, HolimonJ, Orr P: Stage I corpus cancer: Is teletherapy necessary?AmJ Obstet Gyneco1176:777-789,1997 17. Kilgore L, Partridge E, Alvarez R, et al: Adenocarcinoma of

CompleteStagingofEndometrialCarcinoma

the endometrium: Survival comparisons of patients with and without peMc node sampling. Gynecol Onco156:29-33, 1995 18. Morrow C, Bundy B, Kurman R, et ah Relationship between surgical-pathologic risk factors and outcome in clinical stage I and I1 carcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Onco140:55-65, 1991 19. Mohan D, Samuels M, Selim M, et al: Long-term outcomes of therapeutic pelvic lymphadenectomy for stage 1 endometrial adenocarcinoma. Gynecol Oncol 70:165-171, 1998 20. Webb M, Marian A, Galli L, et al: Potential therapeutic role of para-aortic lymphadenectomy in node positive endometrial cancer patients. Gynecol Onco172:447-448, 1999 21. Onda T, Yoshikawa H, Yasugi T, et ah Patients with ovarian carcinoma upstaged to stage Ill after systemic lymphadenectomy have similar smvival to stage IAI patients and superior survival to other stage III patients. Cancer 83:1555-1560, 1998 22. AaldersJ, Abeler V, Kolstad P, et al: Postoperative external irradiation and prognostic parameters in stage I endometrial

23.

24.

25.

26.

27.

7

carcinoma: Clinical and histopathologic study of 540 patients. Obstet Gyneco156:419-426, 1980 Roberts J, Brunetto V, Keys H, et al: A phase III randomized study ofsurgeryvs surgery plus adjunctive radiation therapy in intermediate risk endometrial adenocarcinoma (GOG No. 99). Gynecol Onco168:135, 1998 Ackerman I, Malone S, Thomas G, et al: Endometrial carcinoma: Relative effectiveness of adjuvant irradiation vs therapy reselamd for relapse. Gynecol Onco160:177-183, 1996 Barnes M, Roland P, Straughn M, et al: A comparison of treatment strategies for endometrial adenocarcinoma: Analysis of financial impact. Gynecol Oncol 74:443-447, 1999 Society of Gynecologic Oncologists Medical Practice and Ethics Committee: Practice guidelines: Uterine corpus-endometrial cancer. Oncology 12:122-138, 1998 Fanning J, Firestein S: Cost-effective analysis of complete lymphadenectomy and brachytherapy in early endometrial cancer. Gynecol Onco168:i28, 1998