Cytoreductive Surgery for Advanced and Recurrent Endometrial Cancer: a Review of the Literature

Abstract

There is no standard approach to managing women with advanced or recurrent endometrial cancer; however, there is increasing evidence to support a role for cytoreductive surgery in these women to improve survival outcome. The existing literature is limited by the inherent biases of retrospective studies, as well as small numbers of patients in individual studies; however, the association between optimal or complete cytoreductive surgery in patients with advanced and recurrent endometrial cancer and improved overall survival has been consistent. Furthermore, there is also a strong association between the size of postoperative residual disease and survival; as such, maximal cytoreduction should be the goal in carefully selected patients with advanced or recurrent endometrial cancer who are candidates for surgical management. Additional prospective research is needed in order to further define the role of cytoreductive surgery in advanced and recurrent endometrial cancer, and to develop effective adjuvant therapy to be used postoperatively in order to improve the prognosis in these women.

Keywords

advanced cytoreductive surgery endometrial cancer recurrent uterine papillary serous cancer

Endometrial cancer is the most common gynecologic malignancy in the USA with 40,000 women estimated to be diagnosed in 2009 [1]. Although patients with advanced-stage endometrial cancer represent only 10–15% of all newly diagnosed cases, they account for over 50% of all uterine cancer-related deaths [2,3]. The 5-year survival rates for stage IV disease are as low as 10–20% [4,5]. Patients with metastatic and recurrent disease respond poorly to current therapeutic regimens and, as a result, the optimal management in these women is not well established. Several retrospective studies have examined the role of cytoreductive surgery in these patients, especially when combined with adjuvant radiation or chemotherapy.

Although the role of cytoreductive surgery in endometrial cancer is still evolving, the survival benefit of optimal cytoreduction for ovarian cancer has been confirmed by multiple retrospective and prospective studies, and is now well accepted. The landmark article by Griffiths in 1975 noted the direct correlation in ovarian cancer between the size of residual disease remaining after surgical cytoreduction and overall survival [6]. The survival benefit associated with surgical cytoreduction relies on a number of theories [7 –9]. Reduction in the tumor size will decrease adverse metabolic effects, leading to improved patient comfort and performance status. Tumor debulking can enhance perfusion and drug delivery. Finally, according to the Goldie-Coldman model, decreasing the number of viable tumor cells will decrease the rate of somatic mutations that often perpetuate drug resistance [10].

The question yet to be fully answered is whether these theories of surgical cytoreduction can be extrapolated out to confer a survival advantage in patients with advanced or recurrent endometrial cancer who undergo cytoreductive surgery.

Primary cytoreductive surgery for advanced-stage endometrial cancer

The conceptual approach to cytoreductive surgery for endometrial cancer evolved originally from radiation therapy studies that parenthetically suggested a positive effect of smaller volume, residual disease on overall survival. In 1983, Greer and Hamberger reviewed a series of 31 women with stage III-IV endometrial carcinoma confined to the abdomen who were treated with whole abdominal and pelvic boost radiation [11]. A total of 27 patients with residual disease of 2 cm or less had an absolute 5-year survival rate of 63% compared with 0% for the four patients with residual tumor greater than 2 cm. Martinez et al. similarly studied 25 patients with stage III-IV disease who underwent cytoreductive surgery to 2 cm or less, followed by whole abdominal radiation with nodal boost, and again noted that the size of the residual tumor was prognostic [12]. These studies were not designed to evaluate the effect of primary cytoreductive surgery; however, the results did suggest a correlation between residual disease volume and subsequent survival outcome.

Two additional reviews of advanced-stage endometrial cancer were published in the early 1990s. Pliskow et al. observed 41 cases of stage III-IV endometrial cancer and found that the extent of disease and tumor bulk were prognostic. Patients who received surgery plus radiation had an overall 5-year survival rate of 38% compared with either surgery (8%) or radiation alone (25%) [13]. Goff et al. was the first to specifically investigate the role of residual disease on survival when they reviewed 47 cases of patients with stage IV disease and reported a median survival of 18 months in 29 women with surgically resectable disease versus 8 months in those who did not undergo surgery (p = 0.0001) [14]. However, the size of residual disease was not specified. Nonetheless, cytoreduction was the only statistically significant prognostic variable after multivariate analysis (p = 0.04). Several studies have been conducted since that examined the role of cytoreductive surgery for advanced endometrial cancer, although all of them are limited by their retrospective nature ( Table 1 ) [15 –19].

Table 1.

Retrospective reviews demonstrating that survival is improved after primary cytoreductive surgery for advanced-stage endometrial cancer.

Author	FIGO stage	Optimal definition (cm)	Total patients (n)	Optimal CR (n)	Suboptimal CR (n)	Optimal CR (%)	Optimal median OS (months)	Suboptimal median OS (months)	p-value	Ref.
Chi et al. (1997)	IV	≤2	55	24	21	53	31	12	<0.01	[15]
Bristow et al. (2000)	IVB	≤1	65	36	29	55	34	11	0.0001	[16]
Ayhan et al. (2002)	IVB	≤1	37	22	15	59	25	10	0.001	[17]
Lambrou et al. (2004)	IIIC/IV	≤2	58	42	16	72	18	7	0.001	[18]
Van Wijk et al. (2006)	III/IV	No grossly visible	67	50	17	75	66% 5-year survival	41% 5-year survival	<0.01	[19]

CR: Cytoreduction; FIGO: International Federation of Gynecology and Obstetrics; OS: Overall survival.

The first study to rigorously investigate the role of surgical cytoreduction in stage IV endometrial cancer was conducted by Chi et al., who categorized patients into three groups based on surgical outcome: group I (n = 24) underwent optimal cytoreduction to 2 cm or less; group II (n =21) underwent suboptimal cytoreduction with residual disease greater than 2 cm; and group III (n = 10) had unresectable carcinomatosis [15]. All histologic subtypes were included. The median survival rates were 31 months for group I, 12 months for group II and 3 months for group III (p < 0.01). Notably, there was no statistically significant difference in survival between patients with metastatic disease of 2 cm or less before surgery and those who initially had metastatic disease greater than 2 cm and were subsequently optimally cytoreduced, suggesting that surgical effort and aggressive tumor reduction could potentially increase survival even in advanced disease.

Bristow et al. defined optimal cytoreduction as residual disease of 1 cm or less in a retrospective analysis of 65 patients with stage IVB endometrial cancer, and 55% of patients completed primary cytoreductive surgery with optimal disease status [16]. The histologic subtypes were as follows: 34% endometrioid, 32% serous and 17% mixed. Residual disease, performance status and age were found to be independent predictors upon multivariate analysis. The median survival rate was 34 months for patients undergoing optimal cytoreductive surgery compared with 11 months in patients left with disease greater than 1 cm (p = 0.0001). In the optimally cytoreduced group, patients with only microscopic residual tumor had a significantly longer median survival than patients with optimal but macroscopic residual disease (41 vs 15 months; p = 0.0001), suggesting a role for maximal cytoreduction to no grossly visible residual disease at the time of primary surgery in advanced endometrial cancer.

Ayhan et al. also used the size of 1 cm or less of residual disease to define optimal cytoreduction in a study of 37 patients with stage IVB endometrial cancer and was again able to demonstrate a survival advantage for maximal cytoredection [17]. All histologies were again included, with endometrioid being the most common. The median survival was 25 months in the optimal group compared with 10 months in the suboptimal group (p = 0.001). Further stratification of the optimal group demonstrated a median survival of 48 months if left with only microscopic disease, versus 13 months in patients with optimal but macroscopic residual disease (p = 0.001). On multivariate analysis, optimal cytoreduction, adjuvant cisplatin-radiation therapy and extra-abdominal metastases were significant.

The effect of complete cytoreduction on overall survival, which is supported by both Bristow et al. [16] and Ayhan et al. [17], can be explained through many hypothetical mechanisms that have been described in ovarian cancer. After surgical cytoreduction, patient comfort and performance status are thought to be improved by a decrease in adverse metabolic effects. In addition, debulking is thought to enhance perfusion and drug delivery and decrease the rate of spontaneous mutations that can lead to drug resistance.

More recently, two additional studies have also demonstrated a survival benefit to optimal cytoreduction. Lambrou et al. excluded papillary serous and clear cell histologies when reviewing 58 patients with stage IIIC and stage IV disease [18]. A total of 72% of patients were optimally debulked, as defined by residual disease of 2 cm or less, and had a longer median overall survival compared with suboptimally debulked patients (18 vs 7 months, respectively; p = 0.001). Van Wijk et al. included patients with stage IIIA disease, utilizing no macroscopic disease as the definition of optimal cytoreduction, and again demonstrated a significant survival benefit to optimal surgical cytoreduction [19].

With careful patient selection, cytoreductive surgery in advanced endometrial cancer can be performed with an acceptable morbidity. Ayhan et al. reported that morbidity was severe in 24% of cases and mild in 16% [17]. Interestingly, in the study by Lambrou et al. [18], the proportion of patients with major postoperative complications was greater in patients with suboptimal cytoreductive surgery compared with those with optimal cytoreductive surgery (38 vs 7%, respectively; p = 0.005). The optimal and suboptimal groups had statistically similar radical, debulking procedures and bowel resections, leading the authors to conclude that the increase in morbidity in the suboptimal group was probably secondary to the biology of the disease, rather than the extent of surgery.

In summary, each of the aforementioned studies demonstrated improved overall survival associated with small volume disease remaining after primary resection. Similar to ovarian cancer, maximal surgical cytoreduction to no grossly visible residual tumor was associated with an improved median overall survival and should be the goal for patients with advanced-stage endometrial cancer to maximize response to adjuvant therapies. The percentage of patients that were successfully cytoreduced, whose definition ranged from no grossly visible disease to 2 cm or less depending on the study, was 53–75% [15 –19]. Morbidity was acceptable. These observations highlight the importance of an extensive preoperative work-up and the challenge of predicting which patients are appropriate candidates for an attempt at optimal surgical resection.

Primary cytoreductive surgery for advanced-stage uterine papillary serous cancer

Uterine papillary serous cancer (UPSC) is a more aggressive type of endometrial cancer requiring extended surgical staging (as is the case for ovarian cancer), with approximately 70% of patients found to have stage III-IV disease at the time of initial exploration [20,21]. The 5-year survival for advanced-stage disease is very low, ranging from 0 to 15% [22]. The rarity of this type of tumor makes prospective studies difficult; however, there are several retrospective studies suggesting a role for surgical cytoreduction in the management of stage III-IV disease ( Table 2 ) [23 –27].

Table 2.

Retrospective reviews demonstrating that survival is improved after primary cytoreductive surgery for advanced-stage uterine papillary serous cancer.

Author	FIGO stage	Optimal definition (cm)	Total patients (n)	Optimal CR (n)	Suboptimal CR (n)	Optimal CR (%)	Optimal median OS (months)	Suboptimal median OS (months)	p-value	Ref.
Bristow et al. (2001)	IV	≤1	31	16	15	52	26	10	<0.001	[23]
Memarzadeh et al. (2002)	IIIC/IV	No grossly visible	35	20	15	57	40	10	<0.001	[24]
Moller et al. (2004)	IV	≤1	49	26	23	53	15	8	>0.05	[27]
Thomas et al. (2007)	IIIC/IV	≤1	70	42	28	60	20	12	0.02	[25]
Gardner et al. (2009)	IV	≤1	48	28	20	58	51	13	0.004	[26]

CR: Cytoreduction; FIGO: International Federation of Gynecology and Obstetrics; OS: Overall survival.

Bristow et al. was the first to describe a series of 31 patients with stage IV UPSC undergoing primary cytoreductive surgery and defined optimal as 1 cm or less [23]. A total of 52% of patients were optimally cytoreduced and the median overall survival of optimally cytoreduced patients was 26 months compared with 10 months in the suboptimal group (p < 0.001). Maximal diameter of residual tumor proved to be statistically significant as patients with microscopic disease had a median survival of 30 months compared with 21 months in patients with optimal but macroscopic residual disease (p = 0.004). There was also a survival advantage for patients receiving postoperative platinum-based chemotherapy, underlining the importance of adjuvant therapy after primary surgical intervention. Multivariate analysis demonstrated that cytoreductive surgical outcome was the only statistically significant predictor of survival, although the study was limited by small numbers. Major complications occurred in 13% of patients and minor complications in 39% of cases.

Other studies provide further support for maximal surgical cytoreduction in advanced-stage UPSC [24,25]. Memarzadeh et al. retrospectively reviewed 43 patients with stage III-IV UPSC [24], excluding eight patients with stage IIIA disease from analysis of surgical cytoreduction. In this study, 57% of UPSC were deemed optimally cytoreduced as defined by no grossly visible residual disease. The median survival of patients with only microscopic disease after surgical cytoreduction was significantly improved compared with those left with grossly visible disease (40 vs 10 months, respectively; p < 0.001). In the largest review of 70 patients with stage IIIC-IV UPSC, Thomas et al. utilized 1 cm or less as the marker for optimal cytoreduction and noted an improved survival in the optimal compared with the suboptimal group (20 vs 12 months, respectively; p = 0.02) [25]. The survival advantage increased when surgical resection to microscopic disease was compared with optimal, as defined by 1 cm or less, but grossly visible residual tumor after surgery (51 vs 14 months, respectively; p = 0.002). Importantly, survival was not influenced by the necessity of performing radical procedures to achieve maximal cytoreduction, suggesting that tumor burden at the conclusion of the surgery is more important than the distribution of disease at presentation.

Most recently, Gardner et al. looked at 48 patients with advanced-stage UPSC and found that the disease-specific survival was significantly improved in patients with residual disease of 1 cm or less compared with suboptimally cytoreduced patients (51 vs 13 months, respectively; p = 0.004) [26]. Similar to previous studies, 58% of patients were successfully cytoreduced. After multivariate analysis, optimal debulking, platinum-/taxane-based adjuvant treatment and age were significantly associated with survival.

A multi-institution review by Moller et al. of 49 patients with stage IV UPSC did not find a statistically significant advantage for optimal cytoreduction of 1 cm or less compared with suboptimal cytoreduction (15 vs 8 months, respectively; p > 0.05), but it did demonstrate a trend toward prolonged survival in patients with optimal cytoreduction combined with adjuvant therapy compared with suboptimal cytoreduction combined with adjuvant therapy [27]. Platinum-based adjuvant chemotherapy was associated with a longer median survival compared with those who did not receive platinum chemotherapy, regardless of extent of residual disease (21 vs 2 months, respectively; p < 0.0001). A total of 23% of patients had serious postoperative complications, with no significant difference between the optimal and suboptimal groups.

In summary, specifically looking at advanced-stage UPSC as a distinct histopathologic variant of endometrial cancer, the majority of patients (range: 52–60%) could be optimally cytoreduced and demonstrated an associated survival advantage. Further stratification of size of residual disease supports the goal of maximal cytoreduction in advanced UPSC to achieve an improved clinical outcome. These findings are similar to studies of advanced endometrial cancer that included all histologic subtypes and demonstrated a survival advantage to cytoreductive surgery. The percentage of UPSC in these studies ranged from 8 to 32% [16,17]. The use of platinum-based adjuvant chemotherapy in UPSC also demonstrated a survival benefit, which is logical because systemic chemotherapy as an adjuvant treatment would theoretically be preferred given the propensity of UPSC to recur in the upper abdomen as well as extra-abdominally.

Cytoreductive surgery for recurrent endometrial cancer

The risk of endometrial cancer recurrence ranges from 7.7 to 63.3% depending on specific prognostic factors [28], and treatment options must be tailored based on previously administered treatment and radiation exposure, location and extent of disease, as well as palliative or curative intent. The role of surgical treatment in recurrent endometrial cancer has historically been limited to total pelvic exenteration (TPE) in select patients with vaginal apex recurrences within a previously irradiated field, with reported long-term survival rates of 20–45% but complication rates of 60–80% [29,30]. However, for the majority of patients with recurrence who are not candidates for pelvic exenteration, the existing treatment options have not proven to be very effective. Thus, more recently, investigators have tried to determine if debulking principles could be applied to recurrent endometrial cancer in order to enhance the response to salvage therapies ( Table 3 ) [31 –34]. TPE is not a separate surgical scenario from debulking, but a patient must meet specific criteria to be a candidate for this procedure. Patients who would not be served by a TPE may still benefit from surgical cytoreduction with similar long-term survival to TPE. TPE patients were included in some studies and excluded in others; however, this review aims to investigate the role of surgical cytoreduction in any form and does not seek to specify the extent of surgery necessary to achieve cytoreduction.

Table 3.

Retrospective reviews demonstrating that survival is improved after cytoreductive surgery for recurrent endometrial cancer.

Author	FIGO stage	Optimal definition (cm)	Total patients (n)	Optimal CR (n)	Suboptimal CR (n)	Optimal CR (%)	Optimal median OS (months)	Suboptimal median OS (months)	p-value	Ref.
Scarabelli et al. (1998)	Recurrent	No gross	20	13	7	65	12	Undefined	<0.01	[31]
Campagnutta et al. (2004)	Recurrent	≤1	75	56	19	75	53	9	<0.05	[32]
Awtrey et al. (2006)	Recurrent	≤2	27	18	9	67	43	10	0.01	[33]
Bristow et al. (2006)	Recurrent	No grossly visible	35	23	12	66	39	14	0.0005	[34]

CR: Cytoreduction; FIGO: International Federation of Gynecology and Obstetrics; OS: Overall survival.

Scarabelli et al. was the first to investigate the role of cytoreductive surgery for recurrent endometrial cancer in 1998 [31]. In a review of 20 patients, 65% were able to achieve complete macroscopic resection of disease and had an improved survival compared with women left with measurable disease (12 months vs undefined; p < 0.01). Two patients (10%) had major perioperative complications, and there were two (10%) perioperative deaths.

Other investigations have followed with similar conclusions [32 –34]. Campagnutta et al. examined 75 patients with recurrent endometrial cancer and surgically cytoreduced 75% of patients to 1 cm or less with a significant improvement in overall survival when compared to patients with residual disease greater than 1 cm (53 vs 9 months, respectively; p < 0.05) [32]. A total of 64% of patients underwent complete macroscopic tumor resection. The presence of solitary rather than multiple sites of tumor recurrence was the only clinical characteristic predictive of optimal resection. On multivariate analysis, amount of residual disease, use of postoperative chemotherapy and central pelvic recurrence were significantly associated with improved survival. There was a 31% rate of major surgical complications, mostly hemorrhagic, and an 8% mortality rate for surgical complications after the postoperative period. Awtrey et al. investigated 27 patients and cytoreduced 67% of patient to 2 cm or less and 56% to no grossly visible residual disease [33]. Size of residual disease was the only significant predictor for overall survival, with a median survival of 43 months in patients with 2 cm or less of disease postoperatively compared with 10 months if residual disease measured greater than 2 cm (p = 0.01). In this study, 33% of patients required transfusion, but there were no major perioperative complications or mortalities.

In 2006, Bristow et al. identified 61 patients with recurrent endometrial cancer and were the first to include a nonsurgical treatment group for comparison [34]. A total of 35 patients underwent surgery and had a longer median survival than the nonsurgical group (28 vs 13 months respectively; p < 0.0001). Complete cytoreduction was achieved in 66% of patients and was associated with a median postrecurrence survival of 39 months compared with 14 months for those left with grossly visible residual disease (p = 0.0005). Blood products were given in 29% of cases with no perioperative deaths.

In summary, cytoreductive surgery for recurrent endometrial cancer was possible in 65–75% of patients and was consistently associated with an improved survival in multiple retrospective studies [31 –34]. Although still under investigation, cytoreductive surgery is an appropriate treatment option with acceptable morbidity for carefully selected patients with recurrent endometrial cancer. The reduction in tumor burden would theoretically improve response to subsequent therapy based on the same principles used to explain the survival advantage of cytoreduction in the setting of ovarian cancer.

Limitations of available data

After reviewing the existing literature on the role of cytoreductive surgery in advanced and recurrent endometrial cancer, it is important to recognize some of the limitations. First, the retrospective nature of all of the studies identified carries an inherent selection bias. Next, the numbers are small in each study, given that the majority of endometrial cancer presents at an early stage. Furthermore, the definition of ‘optimal’ for surgical cytoreduction varied among studies. Finally, the adjuvant postoperative treatment regimens for advanced and recurrent endometrial cancer are not standardized, and the variable treatment courses may have impacted survival outcomes.

Conclusion

Despite these limitations, several general conclusions can be made. First, there is consistent evidence to support an intensive surgical approach to achieve optimal primary and salvage cytoreduction in advanced and recurrent endometrial cancer in order to improve survival. Second, analogous to the surgical treatment of ovarian cancer, there appears to be a stepwise improvement in survival based on the size of residual disease remaining postoperatively, with the greatest clinically significant advantage observed for patients cytoreduced to only microscopic residual disease. Third, surgical cytoreduction is associated with an acceptable morbidity and mortality in carefully selected patients; further research is needed to help identify which patients would be appropriate candidates for surgical intervention. Fourth, prospective multi-institutional studies are needed to increase the number of patients enrolled and to further validate the survival advantage associated with surgical cytoreduction that has been demonstrated in numerous existing retrospective studies. Finally, the role of cytoreductive surgery in advanced and recurrent endometrial cancer is only a stepping stone to improved overall survival and relies on the continued development and implementation of effective adjuvant therapy.

Future perspective

Although it will be challenging to conduct, prospective multi-institutional studies are needed to validate the consistent findings of the existing retrospective studies, which suggest that the size of residual disease after surgery has an important impact on survival for patients with advanced and recurrent endometrial cancer. Given the relative infrequency of advanced-stage endometrial cancer, cooperation among institutions will be required to develop prospective studies investigating the role of cytoreductive surgery in endometrial cancer.

With surgical cytoreduction in advanced and recurrent endometrial cancer gaining more ground, it will be important to improve our preoperative assessment to be able to select appropriate candidates who can achieve cytoreduction and benefit with an improved overall survival. A patient's preoperative performance status and existing comorbidities will help to determine which patients would be able to tolerate large-scale surgery. Selection criteria that have demonstrated survival benefit after undergoing secondary cytoreductive surgery for ovarian cancer include: size of postoperative residual disease, specifically complete cytoreduction to no grossly visible disease; longer disease-free interval; younger age; and fewer radiographic sites of recurrence [35 –37]. It is reasonable that the selection criteria used by some for secondary cytoreduction in ovarian cancer can tentatively be extrapolated out for recurrent endometrial cancer and be used as a jumping-off point to specifically study the validity of these criteria in recurrent endometrial cancer.

There are further research avenues of interest to pursue in order to clarify the role of cytoreductive surgery in advanced and recurrent endometrial cancer. How can rates of optimal cytoreduction be maximized? Would there be a role for neoadjuvant chemotherapy in patients with advanced endometrial cancer? After cytoreductive surgery, what is the most effective adjuvant therapy to improve survival? Would there be any role for intraperitoneal chemotherapy? The current management of advanced and recurrent endometrial cancer is variable and includes: hormonal therapy, cytotoxic chemotherapy as single agents and combination regimens, radiation therapy that has been more recently investigated in the forms of intraoperative radiation therapy [38] or CyberKnife robotic radiosurgery [39], and targeted therapies under investigation that inhibit angiogenesis and cellular signaling pathways involved in cell growth and proliferation. Many studies are underway in search of more effective adjuvant therapy in the setting of advanced and recurrent endometrial cancer.

Executive summary

Introduction

Endometrial cancer is the most common gynecologic malignancy in the USA.

Patients with advanced-stage endometrial cancer account for only 10–15% of newly diagnosed cases, but are responsible for over 50% of all uterine cancer-related deaths.

The role of cytoreductive surgery in advanced-stage and recurrent endometrial cancer is still evolving.

Theories regarding the survival benefit of surgical cytoreduction include: decreased adverse metabolic effects leading to improved performance status, enhanced perfusion and drug delivery, and decreased rate of spontaneous mutations that can perpetuate drug resistance.

Primary cytoreductive surgery for advanced-stage endometrial cancer

The first studies to suggest an effect of primary cytoreductive surgery on overall survival in advanced-stage endometrial cancer were from the 1980s and were initially designed to study radiation therapy.

Five retrospective studies, including a total of 272 patients, examining primary cytoreductive surgery in advanced-stage endometrial cancer have consistently demonstrated an increased median overall survival with small volume disease postoperatively.

Similar to ovarian cancer, there is evidence that maximal surgical cytoreduction to no grossly visible residual disease should be the goal to further improve survival.

Primary cytoreductive surgery for advanced-stage uterine papillary serous cancer

Uterine papillary serous cancer (UPSC) is a more aggressive type of endometrial cancer, with approximately 70% of patients found to have advanced-stage disease at the time of initial exploration.

The 5-year survival for advanced stage UPSC is very low at 0–15%.

Five retrospective studies, including a total of 233 patients, specifically looking at primary cytoreductive surgery in advanced-stage UPSC have consistently demonstrated an association with improved median overall survival.

Again, there has been support for maximal surgical cytoreduction to no grossly visible residual disease to further improve overall survival.

The use of systemic platinum-based adjuvant chemotherapy demonstrated a survival benefit, which is logical given the propensity of UPSC to recur distally.

Cytoreductive surgery for recurrent endometrial cancer

The risk of endometrial cancer recurrence ranges from 7.7 to 63.3%.

Surgical treatment in recurrent endometrial cancer has historically been limited to pelvic exenteration in select patients with vaginal apex recurrences within a previously irradiated field; however, the majority of patients with recurrence are not candidates for exenteration.

Four retrospective studies, including a total of 157 patients, concerning cytoreductive surgery in recurrent endometrial cancer have consistently demonstrated an association with improved median overall survival.

Limitations of available data

The existing literature is all retrospective and, therefore, has an inherent selection bias.

Owing to the relative infrequency of advanced and recurrent endometrial cancer, the numbers in each study are small.

Adjuvant postoperative treatment regimens for advanced and recurrent endometrial cancer are not standardized, and the variable treatment courses may have impacted survival outcomes.

Conclusion

There is consistent evidence to support the role of cytoreductive surgery in both advanced-stage and recurrent endometrial cancer.

Analogous to ovarian cancer, there appears to be a stepwise improvement in survival based on the size of residual disease postoperatively, advocating maximal surgical cytoreduction to microscopic disease to achieve the best clinical outcome.

In carefully selected patients, surgical cytoreduction is associated with an acceptable morbidity and mortality.

Future perspective

Prospective, multi-institutional studies are needed to increase the number of patients enrolled and to further validate the survival advantage of surgical cytoreduction in advanced and recurrent endometrial cancer that has been demonstrated in numerous retrospective studies.

Selecting appropriate surgical candidates will rely on improved preoperative assessments, and studies can begin by investigating selection criteria that have demonstrated a survival advantage in secondary cytoreductive surgery for ovarian cancer, such as complete cytoreduction, disease-free interval, age and number of sites of recurrence.

The role of cytoreductive surgery in advanced and recurrent endometrial cancer is only a stepping stone and relies on the continued development of effective adjuvant therapies.

Improvements in healthcare are important in order to be able to provide patients with access to trained gynecologic oncologists who are capable of providing maximal cytoreductive surgical efforts.

Improving postoperative survival outcomes for patients with advanced and recurrent endometrial cancer will also take work in the public health arena in order to provide more of these patients access to trained gynecologic oncologists who would be capable of providing the most complete surgical care. Currently, a major barrier is that the diagnosis of advanced endometrial cancer is rarely made prior to surgery, and the general gynecologist or general surgeon that is often performing the initial surgery would not have the ability to perform the more extensive surgery required for full staging and cytoreduction. Bristow et al. highlighted this important point in the platinum era of advanced ovarian cancer patients, emphasizing that the strongest clinician-driven predictor of survival is surgical outcome [40]. The success rates of cytoreductive surgery for advanced ovarian cancer varied widely depending on the level of extensive formal training that the surgeon had undergone. Similar to advanced ovarian cancer, it would be critical for gynecologic oncologists to be involved in the primary surgery for advanced endometrial cancer. Therefore, we must also work at improving our healthcare system in order to be able to provide more patients with access to expert centers that are capable of performing maximal primary surgical cytoreduction, which would result in improved survival.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

of considerable interest

Jemal

Siegel

Ward

: Cancer statistics, 2008. CA Cancer J. Clin. 58(2), 71–96 (2008).

Behbakht

Yordan

Casey

: Prognostic indicators of survival in advanced endometrial cancer. Gynecol. Oncol. 55(3 Pt 1), 363–367 (1994).

Cook

Lodge

Blake

: Stage IV endometrial carcinoma: a 10 year review of patients. Br. J. Radiol. 72(857), 485–488 (1999).

Vardi

Tadros

Anselmo

Rafla

: The value of exploratory laparotomy in patients with endometrial carcinoma according to the new International Federation of Gynecology and Obstetrics staging. Obstet. Gynecol. 80(2), 204–208 (1992).

Wolfson

Sightler

Markoe

: The prognostic significance of surgical staging for carcinoma of the endometrium. Gynecol. Oncol. 45(2), 142–146 (1992).

Griffiths

: Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst. Monogr. 42, 101–104 (1975).

10.

Landmark article for surgical cytoreduction in ovarian cancer.

11.

Munkarah

Levenback

Wolf

: Secondary cytoreductive surgery for localized intra-abdominal recurrences in epithelial ovarian cancer. Gynecol. Oncol. 81(2), 237–241 (2001).

12.

Gadducci

Iacconi

Cosio

: Complete salvage surgical cytoreduction improves further survival of patients with late recurrent ovarian cancer. Gynecol. Oncol. 79(3), 344–349 (2000).

13.

Eisenkop

Friedman

Wang

: Secondary cytoreductive surgery for recurrent ovarian cancer. A prospective study. Cancer 76(9), 1606–1614 (1995).

14.

Dembo

: Spontaneous mutation to chemotherapy resistance: implications of the Goldie-Coldman model for the management of ovarian cancer. J. Clin. Oncol. 2(12), 1311–1316 (1984)

15.

Greer

Hamberger

: Treatment of intraperitoneal metastatic adenocarcinoma of the endometrium by the whole-abdomen moving-strip technique and pelvic boost irradiation. Gynecol. Oncol. 16(3), 365–373 (1983).

16.

Martinez

Podratz

Schray

Malkasian

: Results of whole abdominopelvic irradiation with nodal boost for patients with endometrial cancer at high risk of failure in the peritoneal cavity. A prospective clinical trial at the Mayo Clinic. Hematol. Oncol. Clin. North Am. 2(3), 431–446 (1988).

17.

Pliskow

Penalver

Averette

: Stage III and stage IV endometrial carcinoma: a review of 41 cases. Gynecol. Oncol. 38(2), 210–215 (1990).

18.

Goff

Goodman

Muntz

: Surgical stage IV endometrial carcinoma: a study of 47 cases. Gynecol. Oncol. 52(2), 237–240 (1994).

19.

First study designed to investigate surgical cytoreduction in advanced endometrial cancer.

20.

Chi

Welshinger

Venkatraman

Barakat

: The role of surgical cytoreduction in stage IV endometrial carcinoma. Gynecol. Oncol. 67(1), 56–60 (1997).

21.

Suggests that primary surgical effort and aggressive tumor reduction could potentially increase survival even in advanced-stage endometrial cancer.

22.

Bristow

Zerbe

Rosenshein

Grumbine

Montz

: Stage IVB endometrial carcinoma: the role of cytoreductive surgery and determinants of survival. Gynecol. Oncol. 78(2), 85–91 (2000).

23.

Supports maximal cytoreduction in primary cytoreductive surgery to further improve survival in advanced-stage endometrial cancer.

24.

Ayhan

Taskiran

Celik

Yuce

Kucukali

: The influence of cytoreductive surgery on survival and morbidity in stage IVB endometrial cancer. Int. J. Gynecol. Cancer 12(5), 448–453 (2002).

25.

Lambrou

Gómez-Marín

Mirhashemi

: Optimal surgical cytoreduction in patients with stage III and stage IV endometrial carcinoma: a study of morbidity and survival. Gynecol. Oncol. 93(3), 653–658 (2004).

26.

van Wijk

Huikeshoven

Abdulkadir

Ewing

Burger

: Stage III and IV endometrial cancer: a 20-year review of patients. Int. J. Gynecol. Cancer 16(4), 1648–1655 (2006).

27.

Slomovitz

Burke

Eifel

: Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases. Gynecol. Oncol. 91(3), 463–469 (2003).

28.

Podratz

Mariani

: Uterine papillary serous carcinomas: the exigency for clinical trials. Gynecol. Oncol. 91(3), 461–462 (2003).

29.

Acharya

Hensley

Montag

Fleming

: Rare uterine cancers. Lancet Oncol. 6 (12), 961–971 (2005).

30.

Bristow

Duska

Montz

: The role of cytoreductive surgery in the management of stage IV uterine papillary serous carcinoma. Gynecol. Oncol. 81(1), 92–99 (2001).

31.

First study specifically addressing uterine papillary serous cancer. Demonstrates a survival advantage with cytoreductive surgery that is increased with maximal cytoreduction.

32.

Memarzadeh

Holschneider

Bristow

: FIGO stage III and IV uterine papillary serous carcinoma: impact of residual disease on survival. Int. J. Gynecol. Cancer 12(5), 454–458 (2002).

33.

Thomas

Mariani

Cliby

: Role of cytoreduction in stage III and IV uterine papillary serous carcinoma. Gynecol. Oncol. 107(2), 190–193 (2007).

34.

Gardner

Leitao

Sonoda

: Surgical debulking improves overall survival for stage IV uterine papillary serous carcinoma. Gynecol. Oncol. 112(2), S89 (2009).

35.

Moller

Gehrig

Van Le

Secord

Schorge

: The role of optimal debulking in advanced-stage serous carcinoma of the uterus. Gynecol. Oncol. 94(1), 170–174 (2004).

36.

Morrow

Bundy

Kurman

: 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(1), 55–65 (1991).

37.

Morris

Alvarez

Kinney

Wilson

: Treatment of recurrent adenocarcinoma of the endometrium with pelvic exenteration. Gynecol. Oncol. 60(2), 288–291 (1996).

38.

Barakat

Goldman

Patel

Venkatraman

Curtin

: Pelvic exenteration for recurrent endometrial cancer. Gynecol. Oncol. 75(1), 99–102 (1999).

39.

Report on pelvic exenteration, which has historically been the only surgical option for select patients with recurrent endometrial cancer.

40.

Scarabelli

Campagnutta

Giorda

: Maximal cytoreductive surgery as a reasonable therapeutic alternative for recurrent endometrial carcinoma. Gynecol. Oncol. 70(1), 90–93 (1998).

41.

First study looking at cytoreductive surgery for recurrent endometrial cancer.

42.

Campagnutta

Giorda

De Piero

: Surgical treatment of recurrent endometrial carcinoma. Cancer 100(1), 89–96 (2004).

43.

Awtrey

Cadungog

Leitao

: Surgical resection of recurrent endometrial carcinoma. Gynecol. Oncol. 102(3), 480–488 (2006).

44.

Bristow

Santillan

Zahurak

: Salvage cytoreductive surgery for recurrent endometrial cancer. Gynecol. Oncol. 103(1), 281–287 (2006).

45.

Oksefjell

Sandstad

Tropé

: The role of secondary cytoreduction in the management of the first relapse in epithelial ovarian cancer. Ann. Oncol. 20(2), 286–293 (2009).

46.

Salani

Santillan

Zahurak

: Secondary cytoreductive surgery for localized, recurrent epithelial ovarian cancer: analysis of prognostic factors and survival outcome. Cancer 109(4), 685–691 (2007).

47.

Chi

McCaughty

Diaz

: Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer 106(9), 1933–1939 (2006).

48.

Dowdy

Mariani

Cliby

: Radical pelvic resection and intraoperative radiation therapy for recurrent endometrial cancer: technique and analysis of outcomes. Gynecol. Oncol. 101(2), 280–286 (2006).

49.

Choi

Cho

Yoo

: Image-guided stereotactic body radiation therapy in patients with isolated para-aortic lymph node metastases from uterine cervical and corpus cancer. Int. J. Radiat. Oncol. Biol. Phys. 74(1), 147–153 (2009).

50.

Bristow

Tomacruz

Armstrong

Trimble

Montz

: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J. Clin. Oncol. 20(5), 1248–1259 (2002).