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Surgical Staging of Endometrial Cancer: Does the Patient Benefit?
GYNECOLOGIC ONCOLOGY ARTICLE NO.
71, 335–339 (1998)
GO985296
EDITORIAL Surgical Staging of Endometrial Cancer: Does the Patient Benefit? James W. Orr, Jr., M.D. Patty Berg Cancer Center, Fort Myers, Florida 33901 Everything should be made as simple as possible, but not simpler. Albert Einstein
One decade ago, in part as a response to the then recent publications detailing the inaccuracy of clinical staging and the importance of extrauterine spread, FIGO designated endometrial cancer a surgically staged malignancy [1– 4]. The initial FIGO clinical staging of endometrial cancer established 40 years earlier was based solely on operability and evidence of extrauterine spread. In 1961, the clinical staging schema was altered to include the potential adverse effect of cervical involvement and bladder or rectal extension. Ten years later, uterine size and tumor grade were incorporated into the clinical staging system. In 1998, FIGO adopted surgical staging, recognizing the importance of myoinvasion, depth of cervical invasion, site of metastasis, and results of peritoneal cytology. While surgical staging was not intended to predicate treatment, few can disagree that the collection of important pathologic information allows an increased understanding of biologic behavior, assists in the detection of extrauterine disease, potentially facilitates management decisions, and certainly improves communication regarding treatment results of patients within a specific surgical stage. These benefits should be welcome in the management of any malignant disease, particularly in one which has demonstrated a near twofold increase in mortality/incidence ratio during the past decade [5]. The adoption of surgical staging has created clinical anxieties as to who best directs management and has prompted questions as to actual patient benefit and necessary extent of procedure. Some argue that this is a “community” disease process and retroperitoneal evaluation is not the standard or even necessary. The importance or benefit of extensive surgical staging has been championed by a number of authors [6 –9], questioned by some [10, 11], and denied by others [12]. In an effort to determine the potential patient benefit derived from surgical staging, a number of simple questions should be addressed.
(4) Which patients should be surgically staged? (5) Does extensive staging or lymphadenectomy have therapeutic value? (6) Can surgical pathologic findings determine further treatment and develop the basis for cost-effective treatment? Practices in clinical medicine are typically based on the integration of published results and strongly influenced by “experience,” personal bias, and opinion. Unfortunately, an individual cannot discriminate between differences in events that occur at a level of 5 to 15%. Therefore, the clinician should exercise care to avoid over- or underweighing the potential risk or benefit when developing a treatment plan based on the bias of their “experience” unless their entire treatment results have been carefully compiled and reviewed. Total incorporation of other “treatment schemes” should also be approached with care as published results from one institution may not be applicable to treatment results at another, secondary to difference in population, clinical experience, or other important factors. While there is no single optimal treatment regimen available for every woman with endometrial cancer, a recent report evaluating current management strategies surveyed a group of gynecologic oncologists [13]. Fifty-four percent of gynecologic oncologists routinely incorporated lymphadenectomy as an important aspect of surgical staging, 43.5% selectively used node dissection during surgical staging, and only 2.3% never used lymphadenectomy during surgical staging. While not prima facie evidence of patient benefit, these results suggest that lymphadenectomy is considered an important aspect of surgical staging by the vast majority of those physicians specifically trained in the management of this disease. (1) What Constitutes an Optimal Staging Procedure or Procedures?
(1) What constitutes an optimal staging procedure or procedures? (2) Do surgical findings alter clinical stage? (3) Can surgical staging be accomplished safely? 335
Creasman et al. [3] and Chuang et al. [14] both report that fewer than 30% of lymph node metastases are clinically detected by palpation. Girardi et al. indicated that nearly half (47%) of the diagnosed lymph node metastases occurred in nodes that were less than 1 cm [15]. These data suggest that retroperitoneal palpation contributes little toward accurate retroperitoneal evaluation, particularly in this obese patient subset. In this regard, selective sampling based on nodal enlargement does not appear to be a 0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
336
EDITORIAL
TABLE 1 Risks of Advanced Surgical Stage Disease in Patients with Clinical Stage I Uterine Cancer Surgical stage Author
I
Creasman et al. [3] Orr [43] Wolfson et al. [37] Kadar [44] Faught et al. [10] Chuang et al. [14] Totals
477/621 (76.8%) 121/168 (72.0%) 106/122 (86.8%) 287/345 (81.8%) 110/269 (81.8%) 112/185 (60.5%) 1339/1744 (76.8%)
Ia
Ib
Ic
32/122 (26.2%)
65/122 (53.5%)
25/122 (20.5%)
35/220 (13.0%) 12/112 (11.9%) 82/454 (18.1%)
114/220 (42.4%) 77/112 (68.6%) 256/454 (56.4%)
69/220 (26.7%) 20/112 (17.6%) 114/454 (25.1%)
Note. Data from [24].
prudent surgical strategy. Some authors have reported utilizing a staging algorithm based on risk of spread as assessed by intraoperative frozen section analysis [16, 17]. Unfortunately, at least 5 to 7% of patients with high-risk factors will be missed by extensive intraoperative frozen section analysis [18]. Postoperative histology is superior to preoperative or intraoperative findings in the prediction of the risk of extrauterine spread [19]. In an evaluation of patients from GOG 33 stages I and II, Hatch reported that 19% (18 of 93) of pelvic node-positive patients had no high-risk histopathologic risk factors detectable at frozen section [20]. Intuitively, extensive sampling (lymphadenectomy) should result in fewer “false negative” evaluations, but at what cost? (2) Do Surgical Findings Alter Clinical Stage? Extensive surgical staging detects extrauterine disease in 23.2% of patients with apparent preoperative clinical stage I disease (Table 1). It is well documented that stage increases in direct correlation to increasing tumor grade or depth of myoinvasion [3]. Pessimists might question the benefit of nodal staging in those women with diagnosed involvement of the retroperitoneum. Published reports indicate that directed treatment of patients with periaortic node metastasis results in survival rates approaching 50% [21, 22]. Recent results record survival in excess of 84% when node-positive patients are treated with a combination of teletherapy and chemotherapy [23]. It would appear that surgical staging detects extrauterine disease in a clinically significant number of women, many of whom can be offered a chance for survival with directed therapies. Failure to detect extrauterine disease portends a dismal prognosis. (3) Can Surgical Staging Be Accomplished Safely? Despite concerns regarding body habitus and existing medical comorbidities, review suggests that the acute surgical morbidity of hysterectomy and lymph node dissection is not dramatically different from that of hysterectomy alone [24]. Operative times of hysterectomy and lymphadenectomy are
typically around 2 h and can be decreased with experience and a consistent operative approach [6, 24]. Retrospective evaluation suggests that the addition of lymph node dissection adds less than 30 min to the operative procedure [25], closely correlating to the usual time required for an extensive frozen section evaluation [16]. Thus, anesthetic risks are not unduly increased with the incorporation of extensive surgical staging. Transfusion risk (as low as 4.8%) is not consistently increased following surgical staging [26]. In contrast, transfusion rates in patients undergoing hysterectomy for the treatment of leiomyoma (#250 g) are in excess of 20% [26]. The incidence of other important acute surgical complications including febrile morbidity, surgical site infection, and wound infection is not significantly increased in those women surgically staged. Postoperative hospital stay is not significantly different and today likely averages 5 days or fewer. Important potential consequences attributable to retroperitoneal evaluation, including thromboembolic events, lymphocysts, and lymphedema, are relatively uncommon. With the exception of a single report [27], there is no obvious significant increased risk of serious thromboembolic phenomena. Clearly these risks are initiated upon opening the retroperitoneal spaces. One might expect a marked increased risk with extensive sampling; however, literature review suggests that this is not apparently true. Regardless, all patients undergoing surgical treatment for endometrial cancer would benefit from thromboembolic prophylaxis [24]. Finally, compared to hysterectomy alone in this same subset of patients, the risk of operative death is not dramatically increased in patients undergoing surgical staging. While recognizing that completing an extensive staging operative procedure presents technical difficulties to the surgical team, current evidence suggests it can be safely accomplished with appropriate preoperative preparation, intraoperative technique, and postoperative care. Operability rates have continually increased and only in the rarest instance should patients not be offered the benefit of a surgical procedure designed for cure.
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(4) Which Patients Should Be Surgically Staged? Questioning the value of extensive staging (lymphadenectomy), Creasman indicated that pelvic node metastasis oc1 curred in 3% of patients with superficially invasive (#3 myometrium) grade I cancers. In another, more recent report, the incidence of pelvic lymph node involvement in women with no myometrial invasion was 4% [28]. Additionally, the risk of recurrence following hysterectomy without myometrial invasion was 5% [28]. While extensive surgical staging does not prevent recurrence, our results [6] as well as others [7, 9] strongly suggest a high likelihood for long-term disease-free survival in those women undergoing a negative lymph node dissection and no further treatment. Nodal involvement increases with grade and depth of invasion; the pelvic surgeon must understand that despite preoperative findings, final pathology will upgrade tumor differentiation nearly 25% of the time [29]. Additionally 10% of grade I cancers are deeply invasive [3]. This information suggests that a significant number of women deemed “low” risk preoperatively will demonstrate high-risk factors intra- or postoperatively. Every treating physician should consider the possible need for retroperitoneal evaluation in all patients undergoing surgical treatment for endometrial cancer. While laparoscopic restaging is always a consideration [30], preoperative preparation for the possibility or need for retroperitoneal evaluation during the primary operation is prudent and cost effective. While extensive staging may be unnecessary in those women with grade I, stage I-A disease, only the rarest operative plan should not include or prepare for possible staging. (5) Does Lymphadenectomy Have Therapeutic Value? This question has plagued every surgical oncologist. Unrecognized microscopic metastasis likely exists in many lymphadenectomy specimens. The ability to prove therapeutic efficacy is inherently undermined by deficiencies in pathologic evaluation of the nodal specimen (i.e., bivalve vs step sections vs immunohistochemical staining) as well as the administration and effects of adjuvant therapy in node-negative women. It is evident that disease does not always recur following dissection of involved retroperitoneal nodes in those not receiving adjuvant therapy. Indirect retrospective evidence of therapeutic benefit includes the report of Kilgore et al. indicating a statistical and clinical survival advantage following extensive surgical staging. This benefit was evident in patients not receiving pre- or postoperative radiation therapy as well as those undergoing postoperative teletherapy and persisted in patients with low- or high-risk factors and those with undifferentiated or deeply invasive cancers regardless of the use of postoperative adjuvant therapy [31]. Therapeutic benefit of node dissection has been implied by Rose et al. [21], who reported an 11% survival in untreated women following resection of involved para-aortic nodes. This argument is further strengthened by the report of Chuang et al.
TABLE 2 Endometrial Carcinoma Nodal Yield Series
Nodal yield
Mohan et al. [9] Orr et al. [6] Fanning et al. [8] Kilgore et al. [31] Wolfson et al. [37]
33 24 28 11 20
[14] suggesting fewer retroperitoneal recurrences following lymph node dissection. These results were confirmed by the Clinical Oncology Society of Australia–New Zealand, whose published results indicated an improved survival of patients undergoing a complete lymphadenectomy [32]. In this journal, Trimble et al. [33] have reported on the impact of pelvic lymph node sampling on 10,066 women with stage I or II endometrioid adenocarcinoma. The results from the National Cancer Institutes Surveillance, Epidemiology, and End Results program suggest an improved 5-year relative survival only in patients with stage I, grade III malignancy undergoing lymph node sampling. Unfortunately, the authors’ inability to control or account for the use of adjuvant radiation therapy clouds their conclusions. The extent of lymph node dissection during surgical staging may be very important. Trimbel et al. were unable to define the extent of sampling, except to report that the median number of nodes samples was 7 (range 1– 40) [33]. In evaluation of recent studies suggesting successful treatment with surgery alone, the nodal yield of patients undergoing lymph node dissection is at least 20 nodes (Table 2). Studies evaluating fewer nodes raise the question of potential sampling error. Larson et al. [7], reporting results of 123 patients with high-risk (cervical involvement, positive cytology) disease treated with lymphadenectomy alone, recorded a survival approaching 90%. In a more recent study Mohan et al. [9] indicated that grade and myoinvasion were not predictors of survival following node dissection and the overall disease-free survival was excellent in those patients undergoing hysterectomy and lymphadenectomy without radiation therapy. The recent review by Podratz et al. of 305 patients [5] suggested that the incidence of recurrence in node-negative patients with moderate or high-risk disease treated with hysterectomy and lymphadenectomy without teletherapy was 6.6%. While arguable, there appears to be some potential therapeutic benefit, particularly if the use of additional adjuvant therapy can be decreased. (6) Can Surgical Pathologic Findings Determine Further Treatment and Develop the Basis for Cost-Effective Treatment? A number of authors have addressed the potential role for adjuvant radiation therapy in patients with apparent (but not
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surgical) stage I disease. Aalders et al.’s [34] important prospective trial reported 18 years ago failed to document a significant survival benefit of adjuvant teletherapy. Morrow et al., evaluating the GOG experience, also reported no obvious survival benefit [35]. Partridge suggested the value of adjuvant pelvic radiation to be indeterminate in patients with stage I-C disease [36]. Wolfson et al., in a retrospective analysis, was unable to detect a beneficial effect of adjuvant treatment on patient survival [37]. Importantly, the risk of recurrence and mortality in patients who have surgical stage I disease is related to the dramatic effect of extrauterine disease. The relative percentage of distal recurrences in patients with surgical stage I disease is extremely high in all series. These results raise the question of the value of adjuvant pelvic teletherapy. In the absence of a clear proven survival benefit, one must evaluate the potential physical and monetary cost of adjuvant teletherapy. The increasing number of publications relating excellent or comparable survival in moderate- or high-risk situations treated with lymphadenectomy alone render it difficult to prescribe adjuvant teletherapy in the absence of documented extrauterine disease. Even radiation therapists have questioned adjuvant use in lieu of therapy reserved for relapse [38]. As important, the risk of severe radiation-induced complications is dramatically increased in patients undergoing extensive surgical procedures with radical retroperitoneal resection [39, 40]. In our recent review, eliminating radiation therapy in this patient subset resulted in a potential savings calculated to be millions [6]. If this schema were extrapolated on a national basis, potential savings could approach hundreds of millions of dollars. In another recent study by Barnes et al. [41], routine lymph node dissection with teletherapy reserved for documented extrauterine disease resulted in a lower percentage of patients receiving radiation with a cost savings of 42% compared to selective sampling based on intraoperative frozen section and the administration of adjuvant teletherapy to those with highrisk uterine factors. Fanning and Firestein, comparing treatment with lymphadenectomy and vaginal brachytherapy to selective lymphadenectomy and teletherapy, reported a cost savings of 39% [42]. Obviously, the benefits of clear forms of therapy are best evaluated by randomized approach study. Although not completely analyzed, the results of GOG-99 evaluation of the benefit of radiation therapy in those women with moderate- to high-risk uterine factor have not indicated significant difference in survival. Review of the answers to the six questions posed in this editorial might suggest that the treatment of endometrial cancer is simple. In every instance the treating physician must understand disease biology and should be able to make pre-, intra-, and postoperative decisions that will enhance survival with minimal risks. This author agrees with Mikuta, who indicated that surgical staging provides the most accurate method of defining external
disease, desirability of and need for postoperative treatment, and a reasonable estimate of prognosis. Obstetricians and gynecologists who discover the disease should strongly consider a consult with gynecologic oncologists to identify the ideal method of treatment. REFERENCES 1. Mikuta JJ: International Federation of Gynecology and Obstetrics. Staging of endometrial cancer 1988. Cancer 71:1460 –1463, 1993 2. DiSaia PJ, Creasman WT, Boronow RC, Blessing JA: Risk factors and recurrent patterns in stage I endometrial cancer. Am J Obstet Gynecol 151:1009 –1015, 1985 3. Creasman WT, Morrow CP, Bundy CN, Homesley HD, Graham JE, Heller PB: Surgical pathologic spread patterns of endometrial cancer: A Gynecologic Oncology Group study. Cancer 60:2035–2041, 1987 4. Lewis BV, Stallworthy JA, Dowdell R: Adenocarcinoma of the body of the uterus. J Obstet Gynaecol Br Commun 77:343–348, 1970 5. Podratz KC, Mariani A, Webb MJ: Editorial: Staging and therapeutic value of lymphadenectomy in endometrial cancer. 70:163–164, 1998 6. Orr JW, Holimon JL, Orr PF: Stage I corpus cancer: Is teletherapy necessary? Am J Obstet Gynecol 176:777–789, 1997 7. Larson DM, Brosic SK, Krawisz BR: Surgery without radiotherapy for primary treatment of endometrial cancer. Obstet Gynecol 91:355–359, 1998 8. Fanning J, Nanvali PJ, Hilgers RD: Surgical staging and high dose rate brachytherapy for endometrial cancer: Limiting external radiotherapy to node-positive tumor. Obstet Gynecol 87:1041–1044, 1996 9. Mohan DS, Samuels MA, Mostafa AS, et al.: Long-term outcomes of therapeutic pelvic lymphadenectomy for stage I endometrial adenocarcinoma. Gynecol Oncol 70:165–171, 1998 10. Faught W, Krepart GV, Lotocki R, Heywood M. Should selective paraaortic lymphadenectomy be part of surgical staging for endometrial cancer? 55:51–55, 1994 11. Carey MS, O’Connell GJ, Johanson CR, et al.: Good outcome associated with a standardized treatment protocol using selective postoperative radiation in patients with clinical stage I adenocarcinoma of the endometrium. Gynecol Oncol 57:128 –144, 1995 12. Belinson JL, Lee KR, Badger GJ, Pretorius RG, Jarrell MA: Clinical stage I adenocarcinoma of the endometrium—Analysis of recurrences and the potential benefit of staging lymphadenectomy. Gynecol Oncol 44:17–23, 1992 13. Maggino T, Romagnolo C, Landoni F, Sartori E, Zola P, Gadducci A: An analysis of approaches to the management of endometrial cancer in North America: A CTF study. Gynecol Oncol 68:274 –279, 1998 14. Chuang L, Burke TW, Tornos C, et al.: Staging laparotomy for endometrial carcinoma: Assessment of retroperitoneal lymph nodes. Gynecol Oncol 58:189 –193, 1995 15. Girardi F, Petru E, Heydarfadai M, et al.: Pelvic lymphadenectomy in the surgical treatment of endometrial cancer. Gynecol Oncol 49:177–180, 1993 16. Malviya VK, Deppe G, Malone JM, et al.: Reliability of frozen section examination in identifying poor prognostic indicators in stage I endometrial adenocarcinoma. Gynecol Oncol 34:299 –304, 1989 17. Zorlu CG, Koscu E, Ergun Y, et al.: Intraoperative evaluation of prognostic factors 34 stage I endometrial cancer by frozen section: How reliable? Acta Obstet Gynecol Scand 72:392–395, 1993 18. Fanning J, Tsukada Y, Piver MS. Intraoperative frozen section diagnosis of depth of myometrial invasion in endometrial adenocarcinoma. Gynecol Oncol 37:47–50, 1990
EDITORIAL 19. Lampe B, Kurzl R, Hantschmann P. Prognostic factors that predict pelvic lymph node metastasis from endometrial carcinoma. Cancer 74:2502– 2508, 1994 20. Hatch K: Endometrial cancer: What is the proper extent of surgical staging? Presented at the 25th annual conference of the Society of Gynecologic Oncologists, 1994 21. Rose PG, Cha SD, Tak WK, Fitzgerald T: Radiation therapy for surgically proven para-aortic node metastasis in endometrial carcinoma. Int J Radiat Oncol Biol Phys 24:229 –233, 1992 22. Corn BW, Lanciano RM, Greven KM, et al.: Endometrial cancer with para-aortic adenopathy: Patterns of failure and opportunities for cure. Int J Radiat Oncol Biol Phys 24:223–237, 1992 23. Onda T, Yoshikawa H, Mizutani K, et al.: Treatment of node-positive endometrial cancer with complete node dissection, chemotherapy and radiation therapy. Br J Cancer 75:1836 –1841, 1997 24. Orr JW, Orr PF, Taylor PT: Surgical staging endometrial cancer. Clin Obstet Gynecol 39:656 – 668, 1996 25. Fanning J, Firestein S: Prospective trail evaluating morbidity of lymphadenectomy in endometrial cancer. Gynecol Oncol 60:126, 1996 [Abstract] 26. Hillis DS, Marchban PA, Peterson HB: Uterine size and risk of complications among women undergoing abdominal hysterectomy for leiomyomas. Obstet Gynecol 87:534 –543, 1996 27. Cliby WA, Clarke-Pearson DL, Dodge R, Kohler M, Rodriguez G, et al.: Acute morbidity and mortality associated with selective pelvic and paraaortic lymphadenectomy in the surgical staging of endometrial adenocarcinoma. J Gynecol Tech 1:19 –26, 1995 28. Takeshima N, Hirai Y, Yamawaki T, Yamauchi K, Hasumi K: Pelvic lymph node metastasis in endometrial cancer with no myometrial invasion. Obstet Gynecol 88:280 –282, 1996 29. Lampe B, Kurzl R, Hantschmann P: Reliability of tumor typing of endometrial carcinoma in prehysterectomy curettage. Int J Gynecol Pathol 14:2– 6, 1995 30. Childers J, Spirtos N, Brainard P, Surwit E: Laproscopic staging of the patient with incompletely staged early adenocarcinoma of the endometrium. Obstet Gynecol 83:597– 600, 1994 31. Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin F, et al.: Adenocarcinoma of the endometrium: Survival compar-
32.
33. 34.
35.
36. 37.
38.
39.
40.
41.
42.
43. 44.
339
isons of patients with and without pelvic node sampling. Gynecol Oncol 56:29 –33, 1994 COSA–NZ–UK Endometrial Cancer Study Groups: Pelvic lymphadenectomy in high risk endometrial cancer. Int J Gynecol Cancer 6:102–107, 1996 Trimble EL, Kosary C, Park RC: Lymph node sampling and survival in endometrial cancer. Gynecol Oncol 71:340 –343, 1998 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 56:419 – 426, 1980 Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al.: Relationship between surgical pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Oncol 40:55– 65, 1991 Partridge EE: Endometrial cancer, changing concepts in therapy. Surg Clin North Am 71:991–1004, 1991 Wolfson AH, Sightier SE, Markoe AM, Schwade J, Averette H, et al.: The prognostic significance of surgical staging for carcinoma of the endometrium. Gynecol Oncol 45:142–146, 1992 Ackerman I, Malone S, Thomas G, Franssen E, Balough J, Dembo A. Endometrial carcinoma-relative effectiveness of adjuvant irradiation vs therapy reserved for relapse. Potish RA, Dusenbery KE: Enteric morbidity of postoperative pelvic external beam and brachytherapy for uterine cancer. Int J Radiat Oncol Biol Phys 18:1005–1010, 1990 Corn BW, Lanciano RM, Greven JM, Noumoff J, Shultz D, et al.: Impact of improved radiation technique, age and lymph node sampling on the severe complication rate of surgically staged endometrial cancer patients: A multivariate analysis. J Clin Oncol 12:510 –515, 1994 Barnes MN, Roland PY, Alvarez RD, et al.: Use of adjuvant radiation therapy in early stage endometrial adenocarcinoma: A decision analysis. Presented at the 29th annual conference of the Society of Gynecologic Oncologists, 1998 Fanning J, Firestein SL. Cost-effective analysis of complete lymphadenectomy and brachytherapy in early endometrial cancer. Gynecol Oncol 68:128, 1998 Orr JW: 1991 Kadar: 1992
71, 335–339 (1998)
GO985296
EDITORIAL Surgical Staging of Endometrial Cancer: Does the Patient Benefit? James W. Orr, Jr., M.D. Patty Berg Cancer Center, Fort Myers, Florida 33901 Everything should be made as simple as possible, but not simpler. Albert Einstein
One decade ago, in part as a response to the then recent publications detailing the inaccuracy of clinical staging and the importance of extrauterine spread, FIGO designated endometrial cancer a surgically staged malignancy [1– 4]. The initial FIGO clinical staging of endometrial cancer established 40 years earlier was based solely on operability and evidence of extrauterine spread. In 1961, the clinical staging schema was altered to include the potential adverse effect of cervical involvement and bladder or rectal extension. Ten years later, uterine size and tumor grade were incorporated into the clinical staging system. In 1998, FIGO adopted surgical staging, recognizing the importance of myoinvasion, depth of cervical invasion, site of metastasis, and results of peritoneal cytology. While surgical staging was not intended to predicate treatment, few can disagree that the collection of important pathologic information allows an increased understanding of biologic behavior, assists in the detection of extrauterine disease, potentially facilitates management decisions, and certainly improves communication regarding treatment results of patients within a specific surgical stage. These benefits should be welcome in the management of any malignant disease, particularly in one which has demonstrated a near twofold increase in mortality/incidence ratio during the past decade [5]. The adoption of surgical staging has created clinical anxieties as to who best directs management and has prompted questions as to actual patient benefit and necessary extent of procedure. Some argue that this is a “community” disease process and retroperitoneal evaluation is not the standard or even necessary. The importance or benefit of extensive surgical staging has been championed by a number of authors [6 –9], questioned by some [10, 11], and denied by others [12]. In an effort to determine the potential patient benefit derived from surgical staging, a number of simple questions should be addressed.
(4) Which patients should be surgically staged? (5) Does extensive staging or lymphadenectomy have therapeutic value? (6) Can surgical pathologic findings determine further treatment and develop the basis for cost-effective treatment? Practices in clinical medicine are typically based on the integration of published results and strongly influenced by “experience,” personal bias, and opinion. Unfortunately, an individual cannot discriminate between differences in events that occur at a level of 5 to 15%. Therefore, the clinician should exercise care to avoid over- or underweighing the potential risk or benefit when developing a treatment plan based on the bias of their “experience” unless their entire treatment results have been carefully compiled and reviewed. Total incorporation of other “treatment schemes” should also be approached with care as published results from one institution may not be applicable to treatment results at another, secondary to difference in population, clinical experience, or other important factors. While there is no single optimal treatment regimen available for every woman with endometrial cancer, a recent report evaluating current management strategies surveyed a group of gynecologic oncologists [13]. Fifty-four percent of gynecologic oncologists routinely incorporated lymphadenectomy as an important aspect of surgical staging, 43.5% selectively used node dissection during surgical staging, and only 2.3% never used lymphadenectomy during surgical staging. While not prima facie evidence of patient benefit, these results suggest that lymphadenectomy is considered an important aspect of surgical staging by the vast majority of those physicians specifically trained in the management of this disease. (1) What Constitutes an Optimal Staging Procedure or Procedures?
(1) What constitutes an optimal staging procedure or procedures? (2) Do surgical findings alter clinical stage? (3) Can surgical staging be accomplished safely? 335
Creasman et al. [3] and Chuang et al. [14] both report that fewer than 30% of lymph node metastases are clinically detected by palpation. Girardi et al. indicated that nearly half (47%) of the diagnosed lymph node metastases occurred in nodes that were less than 1 cm [15]. These data suggest that retroperitoneal palpation contributes little toward accurate retroperitoneal evaluation, particularly in this obese patient subset. In this regard, selective sampling based on nodal enlargement does not appear to be a 0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
336
EDITORIAL
TABLE 1 Risks of Advanced Surgical Stage Disease in Patients with Clinical Stage I Uterine Cancer Surgical stage Author
I
Creasman et al. [3] Orr [43] Wolfson et al. [37] Kadar [44] Faught et al. [10] Chuang et al. [14] Totals
477/621 (76.8%) 121/168 (72.0%) 106/122 (86.8%) 287/345 (81.8%) 110/269 (81.8%) 112/185 (60.5%) 1339/1744 (76.8%)
Ia
Ib
Ic
32/122 (26.2%)
65/122 (53.5%)
25/122 (20.5%)
35/220 (13.0%) 12/112 (11.9%) 82/454 (18.1%)
114/220 (42.4%) 77/112 (68.6%) 256/454 (56.4%)
69/220 (26.7%) 20/112 (17.6%) 114/454 (25.1%)
Note. Data from [24].
prudent surgical strategy. Some authors have reported utilizing a staging algorithm based on risk of spread as assessed by intraoperative frozen section analysis [16, 17]. Unfortunately, at least 5 to 7% of patients with high-risk factors will be missed by extensive intraoperative frozen section analysis [18]. Postoperative histology is superior to preoperative or intraoperative findings in the prediction of the risk of extrauterine spread [19]. In an evaluation of patients from GOG 33 stages I and II, Hatch reported that 19% (18 of 93) of pelvic node-positive patients had no high-risk histopathologic risk factors detectable at frozen section [20]. Intuitively, extensive sampling (lymphadenectomy) should result in fewer “false negative” evaluations, but at what cost? (2) Do Surgical Findings Alter Clinical Stage? Extensive surgical staging detects extrauterine disease in 23.2% of patients with apparent preoperative clinical stage I disease (Table 1). It is well documented that stage increases in direct correlation to increasing tumor grade or depth of myoinvasion [3]. Pessimists might question the benefit of nodal staging in those women with diagnosed involvement of the retroperitoneum. Published reports indicate that directed treatment of patients with periaortic node metastasis results in survival rates approaching 50% [21, 22]. Recent results record survival in excess of 84% when node-positive patients are treated with a combination of teletherapy and chemotherapy [23]. It would appear that surgical staging detects extrauterine disease in a clinically significant number of women, many of whom can be offered a chance for survival with directed therapies. Failure to detect extrauterine disease portends a dismal prognosis. (3) Can Surgical Staging Be Accomplished Safely? Despite concerns regarding body habitus and existing medical comorbidities, review suggests that the acute surgical morbidity of hysterectomy and lymph node dissection is not dramatically different from that of hysterectomy alone [24]. Operative times of hysterectomy and lymphadenectomy are
typically around 2 h and can be decreased with experience and a consistent operative approach [6, 24]. Retrospective evaluation suggests that the addition of lymph node dissection adds less than 30 min to the operative procedure [25], closely correlating to the usual time required for an extensive frozen section evaluation [16]. Thus, anesthetic risks are not unduly increased with the incorporation of extensive surgical staging. Transfusion risk (as low as 4.8%) is not consistently increased following surgical staging [26]. In contrast, transfusion rates in patients undergoing hysterectomy for the treatment of leiomyoma (#250 g) are in excess of 20% [26]. The incidence of other important acute surgical complications including febrile morbidity, surgical site infection, and wound infection is not significantly increased in those women surgically staged. Postoperative hospital stay is not significantly different and today likely averages 5 days or fewer. Important potential consequences attributable to retroperitoneal evaluation, including thromboembolic events, lymphocysts, and lymphedema, are relatively uncommon. With the exception of a single report [27], there is no obvious significant increased risk of serious thromboembolic phenomena. Clearly these risks are initiated upon opening the retroperitoneal spaces. One might expect a marked increased risk with extensive sampling; however, literature review suggests that this is not apparently true. Regardless, all patients undergoing surgical treatment for endometrial cancer would benefit from thromboembolic prophylaxis [24]. Finally, compared to hysterectomy alone in this same subset of patients, the risk of operative death is not dramatically increased in patients undergoing surgical staging. While recognizing that completing an extensive staging operative procedure presents technical difficulties to the surgical team, current evidence suggests it can be safely accomplished with appropriate preoperative preparation, intraoperative technique, and postoperative care. Operability rates have continually increased and only in the rarest instance should patients not be offered the benefit of a surgical procedure designed for cure.
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(4) Which Patients Should Be Surgically Staged? Questioning the value of extensive staging (lymphadenectomy), Creasman indicated that pelvic node metastasis oc1 curred in 3% of patients with superficially invasive (#3 myometrium) grade I cancers. In another, more recent report, the incidence of pelvic lymph node involvement in women with no myometrial invasion was 4% [28]. Additionally, the risk of recurrence following hysterectomy without myometrial invasion was 5% [28]. While extensive surgical staging does not prevent recurrence, our results [6] as well as others [7, 9] strongly suggest a high likelihood for long-term disease-free survival in those women undergoing a negative lymph node dissection and no further treatment. Nodal involvement increases with grade and depth of invasion; the pelvic surgeon must understand that despite preoperative findings, final pathology will upgrade tumor differentiation nearly 25% of the time [29]. Additionally 10% of grade I cancers are deeply invasive [3]. This information suggests that a significant number of women deemed “low” risk preoperatively will demonstrate high-risk factors intra- or postoperatively. Every treating physician should consider the possible need for retroperitoneal evaluation in all patients undergoing surgical treatment for endometrial cancer. While laparoscopic restaging is always a consideration [30], preoperative preparation for the possibility or need for retroperitoneal evaluation during the primary operation is prudent and cost effective. While extensive staging may be unnecessary in those women with grade I, stage I-A disease, only the rarest operative plan should not include or prepare for possible staging. (5) Does Lymphadenectomy Have Therapeutic Value? This question has plagued every surgical oncologist. Unrecognized microscopic metastasis likely exists in many lymphadenectomy specimens. The ability to prove therapeutic efficacy is inherently undermined by deficiencies in pathologic evaluation of the nodal specimen (i.e., bivalve vs step sections vs immunohistochemical staining) as well as the administration and effects of adjuvant therapy in node-negative women. It is evident that disease does not always recur following dissection of involved retroperitoneal nodes in those not receiving adjuvant therapy. Indirect retrospective evidence of therapeutic benefit includes the report of Kilgore et al. indicating a statistical and clinical survival advantage following extensive surgical staging. This benefit was evident in patients not receiving pre- or postoperative radiation therapy as well as those undergoing postoperative teletherapy and persisted in patients with low- or high-risk factors and those with undifferentiated or deeply invasive cancers regardless of the use of postoperative adjuvant therapy [31]. Therapeutic benefit of node dissection has been implied by Rose et al. [21], who reported an 11% survival in untreated women following resection of involved para-aortic nodes. This argument is further strengthened by the report of Chuang et al.
TABLE 2 Endometrial Carcinoma Nodal Yield Series
Nodal yield
Mohan et al. [9] Orr et al. [6] Fanning et al. [8] Kilgore et al. [31] Wolfson et al. [37]
33 24 28 11 20
[14] suggesting fewer retroperitoneal recurrences following lymph node dissection. These results were confirmed by the Clinical Oncology Society of Australia–New Zealand, whose published results indicated an improved survival of patients undergoing a complete lymphadenectomy [32]. In this journal, Trimble et al. [33] have reported on the impact of pelvic lymph node sampling on 10,066 women with stage I or II endometrioid adenocarcinoma. The results from the National Cancer Institutes Surveillance, Epidemiology, and End Results program suggest an improved 5-year relative survival only in patients with stage I, grade III malignancy undergoing lymph node sampling. Unfortunately, the authors’ inability to control or account for the use of adjuvant radiation therapy clouds their conclusions. The extent of lymph node dissection during surgical staging may be very important. Trimbel et al. were unable to define the extent of sampling, except to report that the median number of nodes samples was 7 (range 1– 40) [33]. In evaluation of recent studies suggesting successful treatment with surgery alone, the nodal yield of patients undergoing lymph node dissection is at least 20 nodes (Table 2). Studies evaluating fewer nodes raise the question of potential sampling error. Larson et al. [7], reporting results of 123 patients with high-risk (cervical involvement, positive cytology) disease treated with lymphadenectomy alone, recorded a survival approaching 90%. In a more recent study Mohan et al. [9] indicated that grade and myoinvasion were not predictors of survival following node dissection and the overall disease-free survival was excellent in those patients undergoing hysterectomy and lymphadenectomy without radiation therapy. The recent review by Podratz et al. of 305 patients [5] suggested that the incidence of recurrence in node-negative patients with moderate or high-risk disease treated with hysterectomy and lymphadenectomy without teletherapy was 6.6%. While arguable, there appears to be some potential therapeutic benefit, particularly if the use of additional adjuvant therapy can be decreased. (6) Can Surgical Pathologic Findings Determine Further Treatment and Develop the Basis for Cost-Effective Treatment? A number of authors have addressed the potential role for adjuvant radiation therapy in patients with apparent (but not
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surgical) stage I disease. Aalders et al.’s [34] important prospective trial reported 18 years ago failed to document a significant survival benefit of adjuvant teletherapy. Morrow et al., evaluating the GOG experience, also reported no obvious survival benefit [35]. Partridge suggested the value of adjuvant pelvic radiation to be indeterminate in patients with stage I-C disease [36]. Wolfson et al., in a retrospective analysis, was unable to detect a beneficial effect of adjuvant treatment on patient survival [37]. Importantly, the risk of recurrence and mortality in patients who have surgical stage I disease is related to the dramatic effect of extrauterine disease. The relative percentage of distal recurrences in patients with surgical stage I disease is extremely high in all series. These results raise the question of the value of adjuvant pelvic teletherapy. In the absence of a clear proven survival benefit, one must evaluate the potential physical and monetary cost of adjuvant teletherapy. The increasing number of publications relating excellent or comparable survival in moderate- or high-risk situations treated with lymphadenectomy alone render it difficult to prescribe adjuvant teletherapy in the absence of documented extrauterine disease. Even radiation therapists have questioned adjuvant use in lieu of therapy reserved for relapse [38]. As important, the risk of severe radiation-induced complications is dramatically increased in patients undergoing extensive surgical procedures with radical retroperitoneal resection [39, 40]. In our recent review, eliminating radiation therapy in this patient subset resulted in a potential savings calculated to be millions [6]. If this schema were extrapolated on a national basis, potential savings could approach hundreds of millions of dollars. In another recent study by Barnes et al. [41], routine lymph node dissection with teletherapy reserved for documented extrauterine disease resulted in a lower percentage of patients receiving radiation with a cost savings of 42% compared to selective sampling based on intraoperative frozen section and the administration of adjuvant teletherapy to those with highrisk uterine factors. Fanning and Firestein, comparing treatment with lymphadenectomy and vaginal brachytherapy to selective lymphadenectomy and teletherapy, reported a cost savings of 39% [42]. Obviously, the benefits of clear forms of therapy are best evaluated by randomized approach study. Although not completely analyzed, the results of GOG-99 evaluation of the benefit of radiation therapy in those women with moderate- to high-risk uterine factor have not indicated significant difference in survival. Review of the answers to the six questions posed in this editorial might suggest that the treatment of endometrial cancer is simple. In every instance the treating physician must understand disease biology and should be able to make pre-, intra-, and postoperative decisions that will enhance survival with minimal risks. This author agrees with Mikuta, who indicated that surgical staging provides the most accurate method of defining external
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