The omentum and omentectomy in epithelial ovarian cancer: A reappraisal

Gynecologic Oncology 131 (2013) 784–790

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Review

The omentum and omentectomy in epithelial ovarian cancer: A reappraisal Part II — The role of omentectomy in the staging and treatment of apparent early stage epithelial ovarian cancer Alon Ben Arie a,b, Leah McNally a, Daniel S. Kapp c, Nelson N.H. Teng a,⁎ a b c

Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA Department of Obstetrics and Gynecology, Kaplan Medical Center, Rehovot, Israel Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA

H I G H L I G H T S • Isolated extra-ovarian spread to the omentum is relatively rare. • For staging purposes, omental biopsies may provide as much information as omentectomy. • When omental biopsies might suffice, minimally invasive techniques could play an increased role.

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Article history: Received 31 May 2013 Accepted 11 September 2013 Available online 18 September 2013 Keywords: Ovary Cancer Carcinoma Omentum Omentectomy

a b s t r a c t Objective. This article reviews the literature concerning the role of omentectomy in the staging and treatment of clinically apparent early stage epithelial ovarian cancer. Methods. A review of the English language literature based on a MEDLINE (PubMed) database search using the keywords: ovary, cancer, carcinoma, omentum, and omentectomy. An additional collection of reports was found by systematically reviewing all references from retrieved papers. Results. Historically, the realization that ovarian cancer cells have a predisposition to metastasize to the omentum has led to the inclusion of omentectomy, both for the purpose of accurate staging of ovarian cancer and for its possible therapeutic benefit. In apparently early stage epithelial ovarian cancer, microscopic disease in the omentum is found in 0–22% of the cases; however extra-ovarian disease isolated to the omentum is found in 2–7% of cases at most. There are no specific guidelines as to how much of the omentum should be removed, but pathology studies show that for the purpose of staging and detecting microscopic disease, omental biopsies are probably sufficient in a grossly normal appearing omentum. In cases where adjuvant chemotherapy is planned, the role of omentectomy appears to be primarily for staging, while its therapeutic role remains unclear in microscopic omental disease. Conclusions. In apparent early stage ovarian cancer, the presence of isolated omental metastases is relatively rare. For staging purposes in such cases, random omental biopsies rather than total omentectomy may suffice. Furthermore, chemotherapy appears to effectively treat microscopic disease and therefore if this is already planned the benefit of omentectomy is unclear. © 2013 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . Omentectomy in staging EEOC . . . . . . . . . . . . . . Predictive factors of upstaging and omental metastases in EOC

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⁎ Corresponding author at: Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA. Fax: +1 650 7360902. E-mail address: [email protected] (N.N.H. Teng). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.09.013

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Surgical approach and associated complications of omentectomy The potential therapeutic role of omentectomy in EEOC . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction Epithelial ovarian cancer (EOC) is the most lethal pelvic gynecologic malignancy. An estimated 22,280 new cases of ovarian cancer will be diagnosed in the United States in 2012, with close to 15,500 deaths. Seventy-five percent of women are diagnosed with advanced stage disease [1]. Only about 25% of women with epithelial ovarian cancer have early-stage disease (EEOC) at diagnosis, which is associated with a significantly improved survival rate and may have a different distribution of histopathological subtypes and genetic alterations [2–8]. The standard treatment of EOC includes primary cytoreductive surgery followed by combination platinum/taxane based chemotherapy. However in patients with well to moderately differentiated EOC limited to the ovaries, management may be by surgery alone. According to the gynecologiconcology recommendations and association guidelines, some form of omentectomy is an essential procedure in every case of EOC surgery including cases of EEOC when macroscopically there is no evidence of omental involvement [9,10]. As described in Part I of the review, the inclusion of omentectomy as part of ovarian cancer surgery was based on the awareness that the omentum is a primary site of metastatic spread and, in cases of advanced EOC, is invariably involved by tumor. Given this, the review will not focus on advanced stage EOC, as it has been clearly established that removal of all macroscopic disease is of therapeutic benefit to the patient. In cases of apparent EEOC, studies have shown that visual examination and palpation of pelvic and abdominal tissue cannot always detect occult microscopic metastasis. Hence, it has been recommended that omentectomy should be performed as a component of the surgical staging in these cases as well, both to improve staging accuracy and to gain a possible therapeutic benefit [2–4]. The extent of the omentectomy needed is not well defined and is often unspecified or has varied from study to study. Additionally, despite the recommendation for omentectomy, it is not clear that removing a normal appearing omentum has therapeutic benefit, especially given the better adjuvant chemotherapeutic agents now available. In the first part of the review, we have looked at the history of incorporating omentectomy into the treatment of EOC and have elucidated some of the characteristics and controversies of the omental function and role in cancer. In this second part of the review we evaluate the role and therapeutic significance of performing an omentectomy in EEOC. The other components of the recommended surgical staging, including contralateral oophorectomy and hysterectomy (especially in younger patients wishing to maintain fertility), the number and sites of blind peritoneal biopsies, the value of peritoneal washings, and the extent and sites of retroperitoneal lymphadenectomy are all felt worthy of reevaluation but are beyond the scope of this current review. Similarly the selection criteria of patients with high-risk EEOC for adjuvant chemotherapy as well as the drug selection and number of cycles have been recently reviewed and the recommendations of the NCCN guidelines are adhered to in our postoperative management considerations [10–12]. Additional detailed review of these topics was also felt beyond the scope of this current study.

Methods This article reviews the English language literature for studies on omentectomy in EOC. References for this review were identified through

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searches of PubMed with the search terms “ovary cancer” or “ovarian cancer” combined with the terms “omentum” and “omentectomy” from January 1970 until August 31, 2012. Additional publications were identified via systematic review of all reference lists within publications retrieved from the MEDLINE search. Only papers published in English were reviewed. The search was done by two authors independently and cross over compared. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.

Results Omentectomy in staging EEOC It is well established that the primary route of ovarian cancer spread is transperitoneally, with the majority of EOC cases being diagnosed with intraperitoneal metastases. As mentioned previously, the recognition that almost 30% of apparent EEOC patient are actually at a higher stage due to intraperitoneal or lymph nodes metastases led to the current guidelines for surgical management of EEOC [2,3,7,9,10]. These guidelines include omentectomy as part of the debulking procedure in advanced cases and as part of the staging procedure for evaluation of microscopic disease in apparent EEOC because the omentum has been found to be a common site of intraperitoneal spread. Concerning the role of omentectomy in the evaluation of microscopic disease several issues need to be addressed: 1. Does detection of microscopic metastases require total omentectomy or do more limited procedures such as subtotal (infracolic) omentectomy or even omental biopsies suffice? 2. What is the frequency of omental microscopic disease in apparent EEOC and more specifically what is the frequency of microscopic disease in the omentum as the only site of extra-ovarian spread? 3. What are the predictive factors for omental metastases ? 4. Perhaps most importantly, does omentectomy lead to a different treatment plan and ultimately to a better survival? Reviewing the pathology literature, there are no standardized guidelines as to how the omentum should be evaluated. In fact, in the surgical guidelines from the GOG, which are meant to standardize surgical treatment of patients enrolled in clinical trials, the guidelines for how to perform an omentectomy are as follows: “Careful inspection of the omentum and removal, if possible, of at least the infracolic omentum will be accomplished. At minimum a biopsy of the omentum must be obtained [13].” Even though this statement gives preference to infracolic omentectomy, it also gives validity to omental biopsies. It also means that for patients in these trials, the sampling of the omentum could be a range of procedures. Steinberg et al. found a 100% (32 of 32 patients) correlation between macroscopic evidence of tumor and histologic results; whereas in the normal appearing omentum 22% (12 of 55) of patients had microscopic disease. In half of these patients (11%), the omentum was the only site of disease outside of the ovaries, although only 13% of the patients had lymph node biopsies. The omentum was involved in only 2 of 6 cases with negative nodes which gives an estimate of 3–4% of isolated omental involvement [14]. This study did not specify whether the omental

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Table 1 Upstaging, microscopic omental involvement and isolated omental disease in apparent early stage epithelial ovarian cancer. Author & year (reference)

No of patients in study/no. included

Upstaging (all sites)

Omental involvement

Isolated omentum disease

Knapp 1974 [20] Delgado 1977 [21] Piver 1978 [22] Young 1983 [3] Steinberg 1986 [14] Buchsbaum 1989 Stage I [23] Buchsbaum 1989 Stage II disease [23] Soper 1992 [24] Pomel 1995 [26] Childers 1995 [25] Stier 1996 [23] Schueler 1998 [28] Le 2002 [29] Chi 2005 [30] Doig 2006 [16] Usubütün 2007 [15] Ayhan 2007 [31] Ghezzi (2007) [32] Park 2008 [33] Powless 2009 [34] Shroff 2011 [35] Garcia-Soto 2012 [36]

21/20a 10 31/5b 100 55 97

4 (20%) 2 (20%) 0 (0%) 31 (31%) NA 9 (9%)

1 (5%) 0 (0%) 0 (0%) 6/57 (11%) 12 (22%) 0 (0%)

NA 0 (0%) 0 (0%) NA 4 (4.7%)c 0 (0%)

43

15 (35%)

7/36 (19%)

NA

30 7 14 19 45/36d 94 50 125 68 169 34 36 211 122 86

9 (30%) 0 (0%) 8 (57%) 3 (16%) 8/36 (22%) 34 (36%) 10 (20%) NA NA 53 (31%)e 10 (28%) 7 (19%) 32 (15.1%) 19 (16%) 25 (29%)

2 (7%) 0 (0%) 2 (14%) NA 3/36 (8.3%) NA 0 (0%) 15 (12%) 6 (8.8%) 6 (3.5%) 3 (8.8%) 0 (0%) 4 (2%) 5 (4%) 11 (13%)

NA 0 (0%) 0 (0%) NA 2/36 (5.6%) NA 0 (0%) NA NA NA NA 0 (0%) 3 (1.4%) 4 (3%) 6 (7%)

NA — No available data. a 1 patient had embryonal cancer and was not included. b 31 patients had peritoneoscopy and 5 patients repeat laparotomy. The data from patients with peritoneoscopy were excluded. c Rate is probably lower as metastases to lymph nodes were not evaluated. d Excluding 9 cases with low malignant potential tumors. e Including 19 cases of positive cytology only.

metastases were the only extra-ovarian site of disease, and the majority of patients were not fully staged. Usubütün et al. state, “thorough macroscopic examination is the primary and most important step in detecting omental metastasis.” They further note that this can be done visually, by palpation or by dissection [15]. The efficacy of such inspection is reflected in the findings of Doig and Monahan as well as Usubütün et al., in which the correlation between macroscopic and histologic verification is 98.4% and 97.3% respectively [15,16]. Usubütün et al. found that for microscopic detection, increasing the number of blocks taken of the omentum did not increase the detection rate of tumor in the grossly negative cases. Moreover in all but 2 cases microscopic tumor involvement was present in all of the omental samples. This is in the case despite the fact that the metastatic foci are overall small: between 1 and 5 mm (mean, 3.4 mm). They found a correlation between positive pelvic washings and omental involvement. Tumor grade was also found to be statistically correlated with omental involvement. Only one of 80 (1.25%) ovarian carcinomas metastatic to omentum was grade 1, though they do not specify if the omentum was the sole site of metastasis. Ultimately they conclude that 3 to 5 samples “seem sufficient for appropriate staging.” Admittedly this study is looking at a pathologic analysis of a submitted specimen: however, the process of a pathologist taking samples of a submitted omentum should be akin to a surgeon taking multiple random biopsies of the in situ omentum. By extension, 3 to 5 biopsies could arguably provide the same information for staging purposes as long as the first step of thorough, macroscopic inspection is completed. To date, there has been no study comparing, total omentectomy, subtotal omentectomy or omental biopsies alone for the purposes of staging and treatment. Likely in part because of this lack of information, the gynecologic oncologic associations included omentectomy in their guidelines, but often do not specify how extensive it should be. One major trial strongly advised that an infracolic omentectomy be performed as part of comprehensive surgery staging in early stage ovarian carcinoma [17]. Therefore it is not surprising that in spite of the fact that omentectomy is almost routinely done, the extent of omentectomy varies among

providers. Averette et al., in a 1993 survey, reported that infracolic omentectomy was done in only 59% of patients while Cibula et al. in a more recent survey from Europe reported that in 81% of the cases total omentectomies were being performed [18,19]. Steinberg et al. have noted that while the mean human omental size was 792 cm squared, the mean size of submitted omental specimens in ovarian cancer cases was only 203 cm squared, suggesting that the omentum is incompletely resected and that, likely, omental biopsies were done instead [14]. It is also noteworthy that even in cases where an omentectomy is performed, the standard of care is generally to do an infracolic omentectomy unless there is gross disease in other parts of the omentum. If the omentum is a favored spot for ovarian cancer spread and the goal is to remove this site, then one could argue that a total omentectomy (meaning removal of the greater and the lesser omentum) would actually be the better procedure, as it would remove all of the omentum. However, this is rarely done. The reasoning behind this is presumably that if the omentum is grossly normal, there is no need to perform a bigger procedure and risk complications. When surgeons started performing comprehensive staging it was noted that upstaging occurs in about 30% of apparent stages I–II and omental involvement has been found in 0% to 11% of cases [3,14,20–29]. However in the most recent studies, when comprehensive staging including lymphadenectomy was performed by either laparotomy or laparoscopy, a rate of 0–7% of isolated omental involvement was noted [30–36]. Table 1 summarizes the reported incidence of upstaging in the literature in apparent EEOC, the rate of omental involvement and the cases where the disease in the omentum was the sole site of extra-ovarian spread. Of note, the rate of isolated omental disease in low risk stage I disease is probably even lower, as in many of the apparent EEOC cases the surgical findings were of at least stages IC–IIC. A recent study by Shroff et al. found 5 cases (4%) of omental involvement in apparent EEOC cases and in 4/5 extra-ovarian spread was limited to the omentum. However, in all of these cases the intraoperative presumed stage was IC–IIC. Likewise Powless et al. have found 4 (2%) of patients with apparent EEOC to have microscopic omental tumor involvement, but in all four of these patients the intraoperative stage was of at least IIC [34–36].

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Predictive factors of upstaging and omental metastases in EOC The relatively small number of patients and the heterogeneity of patient selection criteria, patient stage, grade, and histological subtypes, make comparison of studies addressing this issue difficult. Nonetheless several clinical–histopathological factors, including higher apparent initial stage (IC–IIC), higher tumor grade, serous cancer, presence of ascites, and elevated serum CA-125 at the time of staging, have been reported to be predictive of upstaging and specifically omental metastases. In a series of 157 patients with apparent stage I, II, and III EOC, Buchsbaum et al. reported that the incidence of omental metastases was related to the apparent tumor stage prior to comprehensive surgical staging [23]. None of the 96 patients with apparent stage I disease had omental metastases at staging, compared with 19% (7/36) and 65% (30/46) for stages II and III, respectively. They also found a statistically significant increase in omental metastases in patients with serous tumors (p b 0.05) and an association of higher tumor grade and omental metastases for endometrioid EOC that was not of statistical significance. Similarly Doig and Monaghan did an analysis of 318 patients with malignant ovarian tumors of all stages, and reported that the rate of omental metastases was higher for serous tumors (83%, 120/144) than for other histological subtypes of EOC [16]. Usubütün et al. in their evaluation of omentectomy in 134 ovarian cancer patients found that the rate of omental metastasis increased with grade [15]. In only 1.25% (1/80) of grade 1 ovarian cancer cases, omental metastases were found, compared with 26% (19/73) grade 2 and 56% (54/96) grade 3 tumors. Similarly, Shroff et al. in a series of 122 early stage EOC who underwent surgical staging noted that 0% (0/35) of patients with grade I tumors had omental metastases versus 6.6% (4/61) patients with grade 2 or 3 tumors [35]. The presence of these risk factors may raise one's suspicion of occult metastases whereas the absence of these multiple risk factors (e.g., stage IA/B, grade I EOC, see Table 2) may indicate a very low risk of omental metastases. In these cases of very low risk patients, the risk–benefit ratio for omentectomy in the absence of visible disease might weigh in favor of omental biopsies rather than omentectomy. Surgical approach and associated complications of omentectomy Complications from each of the individual components of surgical staging of grossly apparent early stage EOC are rarely reported, except for those associated with pelvic and para-aortic lymph node dissection. It was felt by some that staging procedures including peritoneal washing, infracolic omentectomy, and blind biopsies, were “virtually without complications” [37]. Others note the potential complications of omentectomy including transverse colon or stomach injury, hemorrhage from a gastrocolic ligament ligature, or possible splenic injury [38]. The studies reported on surgical staging and reviewed in Table 1 have a heterogeneous patient population in the timing of the staging (either at time of initial diagnostic surgery or as a second separate staging procedure), the extent of the omental surgery (biopsies, infracolic omentectomy, infragastric omentectomy) and the surgical approach (laparotomy versus laparoscopic). All these factors have potential impact on the rate and grade of both intraoperative complications and postoperative morbidity from surgical staging. For example, Buchsbaum

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et al. reported a high rate of 74 complications in 154 patients, including visceral injury in 23 patients, with 11 injuries to the intestine, 7 to the bladder, 3 to the ureter, 1 to the vena cava, and 1 pneumothorax [23]. It was not possible for these authors to determine how many of the complications resulted from each of the staging procedures per se and which resulted from aggressive cyto-reductive surgical procedures. Lower rates of complications were reported in restaging series that included only patients with original stage I and II EOC, who were thought to have their disease confined to the pelvis and the cancer was felt to have been completely resected at the time of the initial surgery. Nonetheless, comprehensive restaging laparotomy in 30 such patients reported vascular laceration in 6 patients, bowel resection in 4, enterotomy in 2, cystotomy in 1, and abscess requiring drainage in 1 [24]. In addition, incisional separation was noted in 7 patients, febrile morbidity in 4, urinary tract infection in 2, pneumonia in one, and deep venous thrombosis in one patient. Lower rates of complications have been reported for surgical staging performed at the time of the initial surgery compared with secondary staging procedures: 23% vs 77% respectively [28]. Furthermore, surgical complications should also be evaluated in the face of the expanded use of minimally invasive procedures that is increasing in all of the surgical fields. Currently many cancer types are being treated by the laparoscopic or robotic surgery approach because of the benefits of this approach, which include less post-operative pain, shorter hospital stay, and faster recovery time. However in ovarian cancer the introduction of laparoscopy has been less marked. In advanced EOC the spread of tumor to multiple intraperitoneal sites and its bulk limits the use of this surgical technique. In EEOC, which is more rare, there is less experience and hence there is limited evidence on the adequacy, the thoroughness achieved by this approach and its associated complications. Moreover, it is still controversial whether treating EEOC by laparoscopy can cause port site metastases and can induce metastatic spread. Nevertheless a small series of laparoscopic staging of ovarian cancer and laparoscopic re-staging in un-staged patients have been reported, and preliminary data suggest that the minimally invasive approach in experienced hands is comprehensive and safe [25,26,30,32,33,39–44]. However a review of the use of laparoscopy as well as a meta-analysis has suggested that it has equal efficacy as laparotomy in early ovarian cancer [45,46]. Three small studies of EEOC compared laparoscopy to laparotomy and overall 54 patients underwent laparoscopy versus 66 having laparotomy. In all these studies, the lymph node count was the same regardless of the surgical method. In the first study by Chi et al., infracolic omentectomy was performed, and although there was a tendency to remove bigger omenta by the laparotomy approach, the omental size difference was not statistically significant in the two groups [30]. In the second study by Park et al., 50% of the omentectomy procedures were infracolic and 50% infragastric [33]. However the authors do not specify if the surgical route influenced the type of omentectomy done. Park et al. have shown lower complication rates for laparoscopic staging compared to laparotomic staging; however they have noted recurrences in two of 17 patients who underwent laparoscopic surgical staging for stage I disease. Therefore the potential benefits versus the potential risks of minimally invasive approach need to be carefully balanced, particularly in low risk patients with presumed stage IA/B, grade I disease. Only one study compared the outcome of EEOC patients treated by

Table 2 Number of patients with isolated omental metastases in serous and endometrioid EEOC. Author & year (reference)

Microscopic omental involvement

Endometrioid & serous histology

Grade 1

Stage IA/B grade 1

Soper 1992 [24] Doig 2006 [16] Usubutun 2007 [15] Ayahan 2007 [31] Powless 2009 [34] Shroff 2011 [35] Garcia-Soto 2012 [36]

2 15 6 6 4 5 11

NA 7 (46%) 3 (50%) 4 (66%) 4 (100%) 4 (80%) 7 (63%)

0 NA NA NA 1 0 0

0 NA NA NA 0 0 0

NA — Not available.

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laparoscopy or laparotomy, reporting that in the laparoscopy cohort of 33 patients only 2 (6%) had omentectomy performed. This study did not show decreased survival for patients treated by the laparoscopic route and concludes that it seems a feasible and safe procedure [47]. One must consider the pros and cons of minimally invasive surgery before it is adopted as an accepted mode of staging/treating apparent EEOC. The laparoscopic technique may allow better visualization of the peritoneal walls, diaphragmatic surfaces, and liver. However it does so at the cost of losing the tactile evaluation of these areas. It is believed by some that laparoscopic staging may limit the inspection of all serosal bowel surfaces, although quantitative documentation of this was not clearly identified in the literature. Additionally, because the omentum can be large and redundant, it may be more challenging to fully inspect it, ensure that there are no small implants and to perform adequate omentectomy. As mentioned but not proven, the complication rates attributed to the infracolic omentectomy in patients with normal omenta are expected to be very low; although, performing total omentectomy especially with a minimally invasive approach might be associated with increased complication rates. Performance of omental biopsies should be able to be performed quickly and safely by most laparoscopic surgeons. In conclusion the actual rates of serious complications attributed to omentomy alone by either surgical approach, are difficult to determine precisely and have not been well reported. The potential therapeutic role of omentectomy in EEOC Compared to advanced stage EOC, patients diagnosed at an early stage have a significantly better survival. However until about two decades ago the overall 5-year survival rate for patients with EEOC ranged from 50% to 95% in stage I and 30% to 80% in stage II disease [48]. These unfavorable and highly variable results were attributed to two main reasons. The first, and probably the more crucial one, was that about 30% of the apparent EEOC cases actually had advanced stage disease that was inadequately staged [3]. The second possible explanation for the unfavorable outcome was that the standard treatment for early stage disease did not include administration of adjuvant chemotherapy. Of note, it was already recognized that patients with EEOC should be divided into risk groups based on the stage and grade of the disease, and that patients with low-risk stage IA grade 1 tumors treated by surgery alone had an excellent prognosis with an approximately 95% rate of 5year overall survival [4]. Since then, the understanding that a thorough staging procedure including omentectomy, lymphadenectomy, and liberal use of adjuvant chemotherapy in most cases of EEOC – except in stage IA/B well to moderately differentiated tumors – has led to significantly improved survival rates. In the current approach supported by the NCCN guidelines, administering platinum/taxane adjuvant chemotherapy to all high risk EEOC is the rule [9–11]. Given this, it is not clear what additional benefit omentectomy confers. Only one study has evaluated the survival of EEOC patients that underwent omentectomy to those who did not, and it did not find a significant survival benefit for those who had the procedure [49]. This same study did show a survival benefit regardless of chemotherapy administration in patients who had lymphadenectomy; though they note that the p value is marginal (0.0455). An additional study by Dizon and co-workers failed to show a survival advantage associated with the extent of surgical staging in patients with apparent EEOC who received adjuvant chemotherapy [50]. The joint analysis of ICON I and ACTION studies and the analysis of the mature results of the ACTION I trial evaluated the use of adjuvant chemotherapy in clinically apparent EEOC and attempted to access the association of the completeness of the surgical staging with outcome [17,51,52]. One of the major flaws in their analysis was that the majority of the patients were not properly staged. The extent of the surgical staging was not prospectively randomized based on appropriate stratification. Most importantly for our evaluation, the impact of omentectomy in either of these trials cannot be clearly determined. The ICON

1 trial required that all visible tumors be removed, with “thorough surgical staging, where possible” including omentectomy (extent of which was not specified) [52]. In the ACTION trial comprehensive surgical staging was strongly advised and included an infracolic omentectomy. For the retrospective analysis, patients were grouped as optimally staged with only 34% of patients in this group and non-optimally staged. Among the non-optimally staged patients there were three subgroups including a modified staged group (30% of patients) who had undergone an infracolic omentectomy and a minimal staged group (35% of patients) who had partial staging, which could have included an infracolic omentectomy. Therefore up to 56% of the non-optimally staged patients may have had an infracolic omentectomy, and the impact of the omentectomy on outcome was not separately studied in relationship to the potential value of adjuvant chemotherapy. A review of the randomized studies by Trope et al. and a Cochrane meta-analysis on this issue of adjuvant chemotherapy in apparent EEOC emphasized that it is likely that the beneficial effect seen following adjuvant chemotherapy in the high risk group of patients and especially in the unstaged cases is attributable to the mitigating effects of chemotherapy on unrecognized microscopic metastatic disease in apparently EEOC cases [11,12]. Therefore it is still controversial whether completely staged high risk EEOC patients should be treated with adjuvant chemotherapy. Nevertheless most physicians tend to treat with adjuvant chemotherapy all EEOC with the exception of stage IA/B well to moderately differentiated tumors as reflected in recent studies including the GOG 157 where all high risk EEOC patients received adjuvant chemotherapy [53,54]. As stated previously, we do not want to debate the importance of surgical staging, and the data from Cress et al. suggests that lymphadenectomy plays a key role. Instead, we are focusing on the specific role of omentectomy. Based on the data available, if adjuvant chemotherapy is to remain the standard of care, then the evaluation of the omentum is primarily for staging purposes, which arguably can be done with omental biopsies. On the basis of administering adjuvant chemotherapy to all high risk EEOC and withholding it in stage IA/B well to moderately-differentiated cases, the important question arises as to what proportion of early stage patients would be compromised by missing micrometastases if omentectomy is not done. The data available on isolated omental involvement in apparently well to moderately-differentiated stages IA/B tumors is very limited and is summarized in Table 2. Zero of a total of 49 patients with clinically apparent EEOC and omental microscopic involvement had disease that would have been compromised by avoiding omentectomy. An accurate estimate of the proportion of the early stage patients that do not benefit from adjuvant chemotherapy and therefore would potentially be endangered if omentectomy is avoided is not clear. All the largest studies concerning EEOC stratify the patients by histologic type, stage and grade without giving the exact percentage of the specific subgroup of well to moderately-differentiated endometrioid or serous stage IA/B EOC. However a rough estimate from these studies shows that endometrioid and serous histology are found in about 50– 60% of the cases, stage IA/B in 40–50% and grade I–II tumors in about 50–65% of the cases [17,53,55]. Using these numbers, approximately 10–20% of patients with EEOC would have a well to moderatelydifferentiated stage IA/B tumor and hence be candidates for observation without adjuvant chemotherapy. As reviewed above, isolated omental micrometastases are found in only about 5% of such cases, though in actuality this number is probably lower, since this estimate is derived from studies where most of the patients included had at least stage IC–IIC EOC. This number can be further lowered by actually performing random omental biopsies with a probable detection rate of micrometastasis similar to that expected in the omentectomy specimens [15]. A more precise estimate of the incidence of isolated omental involvement in apparent EEOC would require a prospective trial with complete omentectomy as a component of surgical staging and a thorough pathological assessment of the entire omentum as well as of all other surgical staging specimens. The anticipated low incidence of isolated omental metastases would suggest that a large number of

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patients would be required. It should be again emphasized that we have attempted to analyze only the role of omentectomy in patients with apparent EEOC. Similar studies reevaluating the role of contralateral oophorectomy and hystectomy (especially in younger patients wishing to preserve fertility); the extent and sites of blind peritoneal biopsies; the value of peritoneal washings; and the extent and sites of retroperitoneal lymphadenectomy in staging apparent EEOC may be worthwhile [34,56–60]. It was also chosen not to review in detail the use of adjuvant chemotherapy in EEOC as this topic has been recently been explored [10–12]. In conclusion, it seems that the chance of omental micrometastasis in low risk stage I EOC is remote; that omental biopsies can detect them in the rare event that they are present; and that for micrometastases chemotherapy is an effective treatment. Moreover in the last two decades there have been significant improvements in the systemic chemotherapy utilized. There is also the ongoing development and study of promising targeted therapies. These have significantly improved ovarian cancer outcomes and would be expected to also contribute to an improved survival of patients with EEOC with occult microscopic spread of disease. Conclusions Historically the clinical understanding that ovarian cancer cells have an affinity for the omentum, as reflected in omental caking in advanced EOC and microscopic spread in apparent EEOC, has led to the inclusion of omentectomy as a part of the surgical staging and treatment guidelines in all cases of EOC. However to date, in the absence of macroscopic disease, there is no clear evidence that total or infracolic omentectomy is needed to have accurate staging information beyond that which can be obtained from omental biopsies alone. Moreover in cases where adjuvant chemotherapy is planned, it is unclear whether removal of the normal appearing omentum has any significant therapeutic advantage. As we reviewed in Part I, removal of the omentum may have several disadvantages. For one, the omentum provides a defense against intraabdominal infection. Secondly, early on, it appears to have a tumoricidal role. Additionally, the omentum's rich blood supply also gives it a role in both abdominal and extra-abdominal reconstructive surgeries, for example following pelvic exenterative surgeries. Omentectomy itself, especially the more extensive total omentectomy method, may be associated with surgical morbidity, although unfortunately, there are no data specifically on omentectomy-associated complications. Moreover several factors in everyday practice limit our conclusions. These limitations include: inconsistent surgical practice; inconsistent anatomical definition of omentectomy; and the “thoroughness” of the procedure, as the splenic flexure area is frequently omitted. Our main goal in this review has been to summarize the current literature as it pertains to omentectomy in EEOC. Our literature review found that, at most, the risk of isolated metastases to the omentum ranges from 2 to 7%. Although low, this number is not 0%. It is notable that in cases of microscopic disease, chemotherapy seems to eradicate it. However, we fully acknowledge that given this data some practitioners would prefer to remove all tumor possible, even if it is microscopic. Regardless, careful and methodical inspection of the omentum is crucial. Performing omental biopsies rather than infracolic or total omentectomy of the grossly normal omentum may make more providers comfortable using laparoscopic techniques for staging and treatment of early stage ovarian cancer. Conflict of interest statement The authors declare that there are no conflicts of interest.

Acknowledgement Supported in part by the Stanford Gynecologic Oncology Research Fund.

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