Systematic Reviews
ajog.org
Staging for low malignant potential ovarian tumors: a global perspective Sherif A. M. Shazly, MBBCH; Shannon K. Laughlin-Tommaso, MD, MPH; Sean C. Dowdy, MD; Abimbola O. Famuyide, MD
L
ow malignant potential ovarian tumors were first described by Taylor in 1929.1 At that time, this category of ovarian tumors was addressed as semimalignant, a description that may explain the persistence of controversy in their management for the last century. Low malignant potential accounts for 14-15% of all primary ovarian tumors and has been variably placed in a gray zone between benign and malignant.2 Although the prognosis of low malignant potential ovarian tumors remains more favorable than invasive tumors,3 the histological types and microscopic and macroscopic architecture resemble invasive malignant tumors.4,5 Preoperative ultrasonographic diagnosis is reliant on finding typical features of multiloculated or septated cyst with papillary projection; however, up to one third may present as uniocular cysts.6,7 Therefore, 78% of low malignant potential ovarian tumors are encountered and managed by general obstetriciangynecologists, whereas only 10% are managed by gynecological oncologists.8
From the Division of Minimally Invasive Gynecologic Surgery (Drs Shazly, LaughlinTommaso, and Famuyide) Department of Obstetrics and Gynecology, and Division of Gynecologic Surgery (Dr Dowdy), Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN; and Department of Obstetrics and Gynecology, Women Health Hospital, Assiut University, Assiut Egypt (Dr Shazly). Received Dec. 23, 2015; revised March 3, 2016; accepted April 19, 2016. The authors report no conflict of interest. Presented at the European Society of Gynecologic Oncologists, Oct. 25, 2015, Nice, France. Corresponding author: Abimbola O. Famuyide, MBBS.
[email protected] 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2016.04.035
OBJECTIVE: We describe current evidence for staging low malignant potential ovarian
tumors and their conformity to current consensus guidelines and practice from an international perspective. DATA SOURCES: A search of MEDLINE, EMBASE, and SCOPUS databases was conducted for articles published between January 1990 and April 2015. STUDY ELIGIBILITY CRITERIA: Studies on low malignant potential ovarian tumors that evaluated the prognostic value of disease stage, staging vs no staging, complete vs incomplete staging, or discrete components of staging were eligible. Studies that described only crude survival rates were excluded. STUDY APPRAISAL AND SYNTHESIS METHODS: Eligible studies were categorized according to their outcome (disease stage, staging procedure, or discrete staging elements). Data were abstracted using a standard form. Inconsistencies on data abstraction were resolved by consensus among the authors. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: Of 1116 studies, 702 were excluded for irrelevance and 364 for not meeting inclusion criteria. Nine studies were excluded for describing crude survival rates without a comparative conclusion. We found that studies supporting the value of defining disease stage or staging procedures (mostly conducted in northern Europe) included more patients than studies that did not find disease stage or staging useful (predominantly from North America, 4072 vs 3951). Disease stage correlated with survival in 13 of 25 studies, whereas none of the studies that evaluated the value of staging found it beneficial (9 studies, 1979 patients). Studies that evaluated isolated components of staging found no benefit to these procedures. Regional guidelines and consensus reviews drew conclusions based on a limited number of studies that generally originated from the same region. CONCLUSIONS: Although the correlation of stage with survival was mixed, performing staging procedures for low malignant potential ovarian tumors is not supported by the best available evidence. Guidelines in support of staging based their recommendations on a few regional studies and conflict with better-quality data that do not support staging procedures. An international consensus statement is needed to standardize the surgical management of low malignant potential ovarian tumors. Key words: borderline ovarian tumors, surgical staging, systematic review
Management among surgeons, particularly general obstetrician-gynecologists, is inconsistent; 35% do not perform staging biopsies, whereas 9% tend to perform complete staging.8 Full surgical staging has been justified by some because of the difference in prognosis between early and advanced disease stage.9-11 However, the prognostic value of disease stage has not been evident in other studies.12 Furthermore, there is no evidence that adjuvant therapy
improves outcomes for higher staged tumors.13 Accordingly, it is unclear whether defining stage or performing surgical staging is of value. This lack of strong evidence regarding surgical staging weakens practice guidelines and makes them less likely to be followed.8,14 Because disease recurrence or persistence is reported in up to 14% of cases,15 it is important to define an appropriate treatment strategy to
AUGUST 2016 American Journal of Obstetrics & Gynecology
153
Systematic Reviews reduce unnecessary procedures or the need for reintervention.
Materials and Methods Objective The aim of this systematic review is to assess current evidence on surgical staging from a global perspective and to appraise congruence of current consensus statements or guidelines with the best available evidence. This review also summarizes surgeons’ attitude toward staging and to what extent it has been influenced by evidence and clinical guidance. Literature search A search was conducted for studies that addressed the value of staging compared with no staging, complete vs incomplete staging, the value of discrete components of staging, and the prognosis of early vs advanced International Federation of Gynecology and Obstetrics stages of low malignant potential ovarian tumors based on the final pathology report. Based on this review protocol and in collaboration with an expert librarian, a search on MEDLINE, EMBASE, and SCOPUS databases was done for articles published between January 1990 and April 2015. Search key words included borderline ovarian tumors or ovarian low malignant potential tumors and surgical staging or staged or unstaged or lymphadenectomy or omentectomy or peritoneal biopsy or cytology and recurrence or prognosis or outcome or survival. References from related studies and reviews were searched. No language restriction was applied. The detailed search strategy is provided in the Appendix. Eligibility criteria and study selection All abstracts were screened for selection of relevant studies, and full texts were reviewed for eligibility prior to inclusion. Studies were categorized according to whether they described the prognostic impact of early vs late stages, surgical staging vs no staging, complete vs incomplete staging, or discrete staging components (lymphadenectomy, omentectomy, peritoneal biopsy, or cytology).
ajog.org Studies that described only crude survival rates without comparative conclusions were excluded. Sample size alone was not a criterion for exclusion. The outcomes of interest include whether the staging procedure or a knowledge of stage was correlated to the patient outcomes and whether the study origins or the statistical methods applied in these studies influenced their conclusion. To identify consensus statements or guidelines from different regions and congruence with current evidence, we searched MEDLINE, EMBASE, and SCOPUS databases for the articles that contain the following terms: borderline ovarian tumors or low malignant potential ovarian tumors and guidelines or consensus or recommendations. We recorded the publication date, the country of origin, recommendations, and the evidence cited to support these recommendations. For the evaluation of gynecological surgeons’ attitudes toward staging, we searched for the terms the following terms: borderline ovarian tumors or low malignant potential ovarian tumors and survey. We reported the publication date, the country of origin, the surveyed population, and a summary of survey results. Study selection Of 1116 abstracts initially available based on search terms, 702 were excluded for not being relevant to the primary objectives. Additional 364 articles were screened out during review of full texts for not meeting the inclusion criteria. During data extraction, 9 studies were excluded because they provided only crude survival rates without comparative conclusion. Overall, 41 studies with data on 8023 women were eligible (Figure 1). One investigation was considered in the study count but excluded from population size analysis because of the duplication of patients with another study.16 Data abstraction Extraction of the data from the full articles was performed using a standardized form that included authors, year of the study, country of origin, type of study, time frame of data collection, sample size, primary method of
154 American Journal of Obstetrics & Gynecology AUGUST 2016
statistical analysis, duration of followup, outcomes, and conclusions. Data were extracted from the main text, tables, and figures. Inconsistencies between reviewers on study selection and data extraction were resolved by consensus among the authors; discrepancies found were minor. For simplicity, studies were categorized based on their conclusion to either prognostically valuable or prognostically not valuable according to whether a study found disease stage and/or staging procedure(s), useful or not. Observational studies were assessed using the Newcastle-Ottawa Scale.17 Pooled analysis was not feasible because of the heterogeneity of the cohort criteria (spectrum of disease stage, histopathology of the tumor), statistical analysis, duration of followup, and primary outcomes. Furthermore, some studies presented their results as descriptive statements of conclusion rather than quantitative conclusions. An analysis was performed using Microsoft Office Excel 2010 (Microsoft, Redmond, WA).
Results All studies were retrospective and originated from 16 countries (Table 1). Twelve studies were conducted in middle and northern Europe.9,16,18-22,26,27 Another 12 studies originated in southern Europe and the Middle East.28-39 There were 8 studies from North America, 7 studies from Asia,40-46 and 2 from Australia.47,48 Prognostic variables and outcomes were analyzed using a Cox proportional hazards model in 12 studies,16,18,19,29,30,42-44,46,47,49,50 KaplanMaier survival curves in 12 studies,9,20,26,31,33,36,38,40,41,48,51,52 multivariate logistic regression in 3 studies,22,25,53 univariate analyses in 12 studies,21,23,24,27,28,32,34,37,39,45,54,55 and descriptive data in 2 studies.35,56 In these descriptive studies, the authors provided conclusions based on the subjective comparison of outcomes between study groups without statistical analysis. In terms of methodological quality, most studies had Newcastle-Ottawa Scale scores of 5e7, indicating good quality.
Systematic Reviews
ajog.org Comprehensive analysis of evidence Of the 41 included studies, 38 studies provided information about the prognostic value of early vs late disease stages or performing surgical staging, and 13 studies described the value of specific staging elements (10 studies described both overall and specific elements of staging). A summary of included studies is presented in Table 1 and Figure 2. Among the 38 studies, 24 concluded that staging procedures or disease stage were prognostically nonvaluable, whereas 14 studies supported the prognostic value of disease stage or staging procedure (prognostically valuable). The number of included patients was comparable (3951 vs 4072, respectively). The 38 studies were geographically plotted (Figure 3). Nine of the 14 prognostically valuable studies were conducted in northern/middle Europe. By contrast, 7 of the 24 prognostically not valuable studies were conducted in North America and 8 in southern Europe and the Middle East. Comparable numbers of the prognostically not valuable and prognostically valuable studies originated from both Asia and Australia. In terms of analytic approach, prognostically valuable studies predominantly used a Cox proportional hazards model in their analysis (Figure 4). Of 4072 patients included in the prognostically valuable studies, data from 2642 women were analyzed using Cox models vs 800 of the 3951 in the prognostically not valuable studies. In the prognostically not valuable studies, univariate analyses were the most prevalent method of analysis (1620 of 3951 women). The descriptions of staging and complete staging as opposed to no staging and incomplete staging were relatively inconsistent among studies. Because of this inconsistency, staging procedure(s) that were conducted in each of these studies were extracted and analyzed along with isolated procedures from studies of discrete staging elements. The number, the size, and the value of discrete and combined elements of staging in these studies were then plotted in Figure 5. We compared the categories of staging (complete/incomplete, etc) based on how the staging was described in each study.
FIGURE 1
Flow chart of study selection
The figure shows the steps of selection of the eligible studies. Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
Value of disease stage Of the 41 studies, 25 studies addressed the prognostic value of disease stage (I-IV) at the time of surgery including overall survival, disease-free survival, and recurrence. However, they inconsistently defined early and late disease stages, for example, grouping stage I and II as early or II-IV as late (Table 1.I). Thirteen studies concluded that disease stage was prognostically not valuable. However, more patients were included in the 12 studies that found that early stages yielded better prognosis (2619 prognostically not
valuable vs 3490 patients prognostically valuable). Geographically, prognostically valuable studies predominantly originated in northern/middle Europe (Figure 3). Studies from North America were nearly balanced between finding and not finding a difference in prognosis by stage. In terms of statistical analysis, most evidence that supports the prognostic value of disease stage was derived from Cox models. Prognostically not valuable studies were predominantly limited to univariate analyses (Figure 4). Median duration of follow-up was
AUGUST 2016 American Journal of Obstetrics & Gynecology
155
Characteristics of included studies Author
Year
Country
Data collection Sample Duration of Type of study frame size follow-up
Statistical method
Outcome
Comparison groups
Quality Conclusion of studya
Stages I-II and stage III
PNV
6
Studies that analyzed the value of disease stages (early vs late) Loizzi et al28 2015
Italy
Retrospective
January 1991 to December 2011
55
N/A
Univariate analysis
Disease-free survival time and rate
559
N/A
Cox regression
Progression-free Stages II-III vs survival stage I
PV
7
PNV
5
2015
Germany
Retrospective
1998e2008
Menczer et al39
2012
Israel
Retrospective
March 1, 1994, 225 to June 30, 1999
13 y survival was considered
Univariate analysis
13 y survival rate
Germany
Retrospective
1998 to 2008
N/A
Cox regression
Progression-free Stage I vs II/III survival
PV
7
Italy
Retrospective
January 1985 to 209 August 2010
Mean, 52.7 mo (range, 4-240 mo)
Cox regression
Disease-free survival
Stage I vs II/III
PNV
6
Ewald-Riegler 2012 et al19
Germany
Retrospective
1997 and 2000 158
Median, 42.12 mo
Cox regression
Relapse-free survival
Staging I vs II/III
PV
6
Tang et al47,c 2012
Australia, Retrospective Hong Kong, The Netherlands
1985 and 2008 940
Median, 53.9 mo (range, 0e60 mo)
Cox regression
Disease-free survival and overall survival
Stage I vs II-IV
PV
6
Shih et al54
2011
United States
Retrospective
1979e2008
266
Median, 44.4 mo (range, 0e273.6 mo)
Univariate analysis
3 y overall survival
Stages I, II, and III/IV
PNV
6
Tsai et al46
2011
Taiwan
Retrospective
2000e2006
61
Mean, 56.5 mo (range, 12e103 mo)
Cox regression
Disease-free survival
Stage Ia vs Ib-III
PNV
6
Park et al42
2011
Korea
Retrospective
1990e2010
130
Mean and median, 90 and 79 mo (range, 5e236 mo)
Cox regression
Disease-free survival
Stage I vs II/III
PNV
7
Poncelet et al22
2010
France
Retrospective
1990e2000
317
Multivariate Mean, 34.4 2.6 mo (women followed up by logistic CA125) and 40 5.1 mo regression (women who were not)
Recurrence rates
Stage Ia vs other stages
PV
7
Park et al43
2009
Korea
Retrospective
April 1989 to May 360 2008
Median, 70 mo (range 3e216 mo)
Cox regression
Disease-free interval
Early stages (I/II) vs late stages (III/IV)
PV
6
Lenhard et al20
2009
Germany
Retrospective
1983 to 2006
Mean, 9.6 6.6 y
Kaplan-Meier curve (log-rank test)
Overall survival (5 and 10 y survival rates), relapse rate
Stage Ia vs higher stages
PNV
6
Bois et al18,b 2013 Ferrero et al.28
2012
Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
950
113
Stage I and stage II/III
(continued)
ajog.org
Trillsch et al 16,b
Systematic Reviews
156 American Journal of Obstetrics & Gynecology AUGUST 2016
TABLE 1
Characteristics of included studies (continued) Year
Country
Data collection Sample Duration of Type of study frame size follow-up
Statistical method
Outcome
Kane et al23
2009
France
Retrospective
January 1973 to 168 February 2006
Median, 57 mo (range, 1e437 mo)
Univariate analysis
Recurrence-free Stage II and interval stage III
PNV
5
De Iaco et al30 2008
Italy
Retrospective
January 1985 to 168 June 2006
Mean, 60.5 (range 4-240 mo)
Cox regression
Recurrence rate
Stage I and stage III
PNV
6
Ren et al48
2008
China
Retrospective
January 2001 to 234 June 2007
Median, 40 mo (range, 8e78 mo)
Cox regression
Disease-free survival
Stages I, II, and III
PV
7
Cusido´ et al37 2007
Spain
Retrospective
January 1990 to 457 December 1997
Mean, 88 41.21 mo
Univariate analysis
Recurrence
Stages I, II, and III
PNV
5
Yokoyama et al40
2006
Japan
Retrospective
1994e2003
Median, 57 mo (1e126 mo)
Disease-free Kaplan-Meier curve (disease- survival and free survival) and recurrence multinomial logistic regression (for recurrence)
Stage I vs II-IV
PNV
5
Romagnolo et al31
2006
Italy
Retrospective
January 1992 to 113 June 2004
Median, 40 mo for laparotomy, 47 mo for laparoscopy
Kaplan-Meier curve (log-rank test)
Progression-free Stages Ia, Ib-Ic, survival (at 10 y) II, and III
PV
6
Camatte et al24
2002
France
Retrospective
January 1969 to December 2000
68
Median, 71.5 mo (range, 3-313 mo)
Univariate analysis
5 y recurrence rate
PV
5
Gershenson et al50
1998
United States
Retrospective
1956 through mid-1996
39
Median, 111 mo
Cox regression
Overall survival Stage II vs IIIe IV and progressionfree survival
PNV
7
Tamakoshi et al41
1997
Japan
Retrospective
Jan. 1, 1980 to 150 Dec. 31, 1994
Mean, 61 mo (range, 2e140 mo)
Kaplan-Meier curve (log-rank test)
Survival rates
Stage I vs IIeIII
PV
6
Sykes et al48 1997
Australia
Retrospective
1972e1994
234
Mean, 54 m (range, 2-234 mo)
Kaplan-Meier curve
Recurrence rate and overall survival
Stage I vs IIeIII
PNV
6
Kærn et al9
Norway
Retrospective
1970e1982
370
Median, 127 m (range, e218 mo)
Kaplan-Meier curve (log-rank test), Cox regression
Relapse, disease- Stage I and free survival and stage IIeIII corrected survival
PV
5
United States
Retrospective
1997e1984
200
Mean, 120, median, 134.4 mo (range, 48-324 mo)
Kaplan-Meier curve (log-rank test)
Survival rates (20 y)
PV
5
1993
Leake et al52 1992
Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
124
Comparison groups
Stage I vs stage II/III
Stage, I, II, and III
Quality Conclusion of studya
(continued)
157
Systematic Reviews
AUGUST 2016 American Journal of Obstetrics & Gynecology
Author
ajog.org
TABLE 1
Characteristics of included studies (continued) Author
Year
Country
Data collection Sample Duration of Type of study frame size follow-up
Statistical method
Outcome
Comparison groups
Quality Conclusion of studya
Studies that evaluated the value of complete vs incomplete staging Denmark
Retrospective
Jan. 1, 2007, to Dec. 31, 2011
75
Median, 28.7 mo (range, 3.8-67.1 mo)
Univariate analysis
Recurrence
Complete staging was defined as radical surgery, cytology, multiple peritoneal biopsies, and omentectomy. Incomplete staging was defined as the lack of 1 or more of these steps.
PNV
6
Romeo et al38 2013
Spain
Retrospective
January 1992 to December 2002
46
Median, 64.8 mo (interquartile range, 30 to 72 mo)
Kaplan-Meier curve (log-rank test), Cox regression
Relapse-free survival
PNV Incomplete staging included lack of infracolic omentectomy, incomplete exploration of the entire cavity, and the paucity of peritoneal biopsies and peritoneal washings.
7
Azuar et al25 2013
France
Retrospective
January 1990 to 142 December 2007
Mean, 80.5 mo (range, 12e168 mo)
Multivariate Relapse logistic regression
PV Optimal staging was defined as inspection of the peritoneal cavity, an infracolic omentectomy, peritoneal biopsies, and appendectomy for mucinous tumors (incomplete staging was not defined).
6
Avril et al21
Germany
Retrospective
1998e2008
Mean, 63 mo, median, 56 mo (range 0e165 mo)
Univariate analysis
PV Recurrence-free Complete staging includes omentectomy, and overall multiple peritoneal survival biopsies and peritoneal cytology (incomplete staging was not defined).
5
Kristensen et al27
2014
2012
Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
70
Systematic Reviews
158 American Journal of Obstetrics & Gynecology AUGUST 2016
TABLE 1
(continued)
ajog.org
Characteristics of included studies (continued) Data collection Sample Duration of Type of study frame size follow-up
Statistical method
Anfinan et al51 2011
Canada
Retrospective
January 1994 to 138 December 2005
Median, 37 mo (range, 39e154 mo)
Kaplan-Meier Overall survival curve (Log-Rank and test) recurrence-free survival
PNV Complete staging included inspection of all peritoneal surfaces and peritoneal washing, infracolic omentectomy, multiple peritoneal biopsies, and pelvic and paraaortic LA. Incomplete staging was considered when at least 1 of these procedures was missed.
5
Koskas et al26 2011
France
Retrospective
1997 to 2004
97
Median, 48 mo (range, 3e182 mo)
Kaplan-Meier curve
Recurrence
Complete staging was PNV defined as at least peritoneal cytology sampling, peritoneal biopsies and omentectomy, or omental biopsy (incomplete staging was not defined).
4
Di Re et al32
Italy
Retrospective
January 1975 to December 1991
34
Mean, 108 mo, median, 86 mo (range, 20e222 mo)
Univariate analysis
Survival and recurrence
Complete staging was PNV defined as peritoneal washing, cytopathology, total hysterectomy. and bilateral oophorectomy, infracolic gastrocolic omentectomy (if omentum is involved), appendectomy, random peritoneal biopsies and paraaortic and pelvic LA. Incomplete staging ranged from unilateral oophorectomy to any staging procedure that was not complete.
5
Year
1994
AUGUST 2016 American Journal of Obstetrics & Gynecology
Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
Outcome
Comparison groups
Quality Conclusion of studya
(continued)
159
Systematic Reviews
Country
Author
ajog.org
TABLE 1
Characteristics of included studies (continued) Author
Year
Country
Data collection Sample Duration of Type of study frame size follow-up
Statistical method
Outcome
Comparison groups
Quality Conclusion of studya
Studies that evaluated the value of staging over no stagingd Retrospective
N/A
539
Median, 36 mo (range, 1-120 mo)
Kaplan-Meier curve (log-rank test)
Overall survival
Staged vs unstaged (staged patients are those who had peritoneal washing, omentum, and peritoneal biopsies with or without LA)
PNV
5
Wong et al45 2007
Singapore
Retrospective
January 1991 to 247 December 2004
Mean, 21 mo (range 2e140 mo)
Univariate analysis
Recurrence, mortality rate
Staged vs unstaged (staged patients had peritoneal washings, adnexectomy, peritoneal biopsies, and omental biopsy)
PNV
5
SuhBurgmann49
2006
United States
Retrospective
1982e2004
193
Mean, 82.8 mo (range, 6e230.4 mo)
Cox regression
Disease-free survival
Staged vs unstaged (staging refers to peritoneal and/or omental biopsies, lymph node biopsies and appendectomy)
PNV
7
Wingo et al56 2006
United States
Retrospective
April 2003 to May 2005
32
N/A
Descriptive data Recurrence
PNV Staged vs unstaged (staging included cytology, omentectomy, peritoneal biopsy and in most patients, pelvic/paraaortic node dissection)
5
Rao et al53
2004
United States
Retrospective
January 1984 to 248 June 2003
N/A
Logistic regression
Recurrence
Staged vs unstaged (staging was not defined)
PNV
6
Winter et al55 2002
United States
Retrospective
1979e1997
Mean, 78 50.4 mo
Univariate analysis
Recurrence and mortality rates
Staged vs unstaged (staging referred to hysterectomy and bilateral salpingooophorectomy, pelvic or paraaortic LA, omental biopsy, peritoneal biopsies, and cytological washings)
PNV
6
2013
Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
93
(continued)
ajog.org
Turkey
Guvenal et al33
Systematic Reviews
160 American Journal of Obstetrics & Gynecology AUGUST 2016
TABLE 1
Systematic Reviews comparable between the prognostically not valuable and prognostically valuable studies (58.8 months vs 57.5 months, respectively). Value of surgical staging Complete vs incomplete staging. Seven studies addressed the impact of complete vs incomplete staging on survival and recurrence; 5 of these concluded that complete staging did not improve the outcome in comparison with incomplete staging (n ¼ 390 women included in these 5 studies). The 2 studies that found that staging improved outcomes included 212 women and originated in middle/northern Europe in 2012 and 2013 (Figure 3). Studies from North America and southern Europe found no difference in outcomes between complete and incomplete staging. Overall, Cox models were not used in any of the 7 studies; rather, Kaplan-Meier models was the predominant statistical analysis used for analysis (Figure 4). The range of postoperative follow-up in prognostically not valuable studies was 28.7e138 months vs 70e142 months in prognostically valuable studies.
Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
Quality of the studies in terms of bias risk was assessed using the Newcastle-Ottawa Scale. Numbers given refer to the total number of stars; b These studies extracted data from a single database and yielded similar evidence. Only 1 study was included in the analysis (according to sample size); c In this study, the distribution of participation in sample size was as follows: Australia (67.45%), Hong Kong (16.81%), and The Netherlands (15.74%); d Menczer et al,39 De Iaco et al,30 and Sykes et al48 are also included under this section; e Guvenal et al,33 Romeo et al,38 Shih et al,54 Tsai et al,46 Rao et al,53 and Camatte et al24 are also included under this section.
LA, lymphadenectomy; N/A, not available; PNV, prognostically not valuable; PV, prognostically valuable.
January 1982 to 100 December 2004 Retrospective Turkey Ayhan et al36 2005
a
Cytology not 6 valuable Kaplan-Meier curve It ranged from 1 to 157 mo
Overall disease-free survival
Peritoneal cytology
5 LA not valuable LA Descriptive data Lymph node metastasis, upstaging Median, 54.6 mo (range, 12e96 mo) 1998e2007 Turkey 2008 Pirimoglu et al35
Prospective
25 2003e2009 Retrospective Turkey Baran et al34 2011
Studies that evaluated the value of staging elementse
57
Recurrence Univariate analysis
Outcome Statistical method Data collection Sample Duration of Type of study frame size follow-up Country Year Author
Characteristics of included studies (continued)
TABLE 1
Mean, 25,6 mo (range, 10e82 mo)
LA
Comparison groups
LA not valuable
6
Quality Conclusion of studya
ajog.org
Staging vs no staging. The value of staging vs no staging was directly evaluated in 9 studies. All studies found that staging did not influence disease-free survival or overall survival (1979 patients). These studies were conducted in North America, southern Europe, Asia, and Australia. No studies were conducted in middle/northern Europe (Figure 3). Evidence was principally derived from Kaplan-Meier curves (n ¼ 773), univariate analysis (n ¼ 565), and Cox models (n ¼ 361) (Figure 4). Median length of follow-up was 57 months. Discrete staging elements. Among the 41 included studies, 13 studies assessed the impact of discrete staging elements (Figure 5). Eight of these studies evaluated the value of lymphadenectomy during surgical management of low malignant potential tumors.24,33-35,38,46,53,54 Seven studies failed to find an association between lymphadenectomy and survival, whereas in 1 investigation lymphadenectomy was AUGUST 2016 American Journal of Obstetrics & Gynecology
161
Systematic Reviews
ajog.org
FIGURE 2
Origin and conclusion of included studies, guidelines, and surveys
This figure is a chronological illustration of the geographic distribution and the type of statistical analysis of the included studies in relation to clinical guidance and surgeons’ surveys. The figure demonstrates the characteristics of studies that found disease stage or staging procedure either prognostically valuable or not valuable. The chart summarizes the total size of the population studied per year, the type of statistical analysis used, and the origin of these studies. Guidelines (red boxes) and practice surveys (green boxes) that were conducted during this period were presented on either side according to their conclusion. Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
FIGURE 3
Geographical distribution of included studies according to their conclusion
Included studies are graphically presented according to the origin of the study. Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
162 American Journal of Obstetrics & Gynecology AUGUST 2016
Systematic Reviews
ajog.org
FIGURE 4
Type of statistical analysis of included studies according to their conclusion
Included studies are graphically presented according to the statistical approach. Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
associated with a longer relapse-free survival compared with no lymphadenectomy (P ¼ .04). The 7 studies were conducted in northern Europe, southern Europe, North America, and Asia using Kaplan-Meier curves (n ¼ 539), a univariate analysis (n ¼ 291), and a Cox model (n ¼ 61). The study that supported the value of lymphadenectomy was conducted in Spain using KaplanMeier analysis (n ¼ 46). The value of obtaining peritoneal cytology was investigated in 4 studies; all showed no impact on disease outcomes.16,23,36,43 Two studies were conducted in northern Europe, 1 in southern Europe, and 1 in Asia. Of the 1187 patients included in these studies, 919 were analyzed using Cox models. Biopsies from the peritoneum were
tested in 2 studies; neither supported it as a prognostic factor.16,27 They were both conducted in middle/northern Europe using a Cox model (559 of 634) and a univariate analysis (75 of 634). Lastly, omentectomy was reported in 1 study in middle/north Europe (Germany) demonstrating better progression-free survival compared with no omentectomy.16 One study did not find hysterectomy to be associated with outcome (n ¼ 225),39 whereas 1 investigation did (n ¼ 25),34 and both utilized univariate analysis. Clinical guidance and surgeons’ practice Six relevant guidelines or consensus statements were identified between 1990 and 2015 (Table 2). Three of these
guidelines recommended complete staging for low malignant potential ovarian tumors in 2007 (United States),57 2009 (Australia),58 and 2014 (international, predominantly from Germany).59 The other 3 concluded that staging is not indicated; these guidelines were published in 2000 (Canada),60 2011 (Canada),61 and 2014 (United States).62 In the same time frame, we identified 3 surveys of surgeons’ attitude from the United States (1999, 2000)8,14 and Germany (2009).63 All indicated that the majority of surgeons perform complete staging. These are shown in Figure 2 (consensuses are shown as red boxes, surveys as green boxes).
Comment This systematic review comprehensively appraised evidence of the surgical
AUGUST 2016 American Journal of Obstetrics & Gynecology
163
Systematic Reviews
ajog.org
FIGURE 5
The value of single and combined staging steps
Evidence on the prognostic rule of single and combined staging steps is illustrated according to the size of the study population in each study. Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
management of low malignant potential ovarian tumors. Included studies reflected a noticeable regional trend; most studies that found no benefit in staging originated in North America, particularly in the United States, whereas the majority of studies that supported staging were conducted in middle/northern Europe, particularly Germany and France. For studies that described the value of disease stage, a nongeographical explanation of this variation may be the manner in which data were analyzed. Studies that found prognostic value in disease stage predominantly used Cox models, whereas studies that found no prognostic difference by disease stage used a univariate analysis. Cox models are generally more accurate for prognostic appraisal than univariate analyses because of the considerable influence of survival time and confounders. One of these confounders is the use of total abdominal hysterectomy and bilateral salpingo-oophorectomy vs conservative surgery (cystectomy or unilateral salpingectomy). Unlike invasive ovarian
cancers, hysterectomy and contralateral oophorectomy were not considered part of the routine staging procedure and were usually tested separately in prognostic models in most studies. However, these studies described prognosis of disease stage rather than the staging procedure itself. Studies that compared complete with incomplete staging varied by region of study origination. Because complete staging has various definitions, geographical variation in the study findings may reflect the differences in the extent of staging procedures in these countries. Interestingly, individual elements of staging such as lymphadenectomy or obtaining peritoneal cytology were not found to influence survival, including studies conducted in northern/middle Europe that generally support staging. The most important evidence comes from the 9 studies that assessed surgical staging vs no staging; none showed staging to be beneficial. Furthermore, they may be more informative, considering that staging vs no staging is more distinct than complete vs incomplete staging and
164 American Journal of Obstetrics & Gynecology AUGUST 2016
early vs late stages, which were inconsistently defined among studies. These studies were conducted globally in the United States, Asia, Australia, the Middle East, and southern Europe but not in middle/northern Europe and were analyzed using a variety of statistical methods, including Cox regression. Because these studies were retrospective, they reflect surgical practice in the region and the time of the study. Therefore, a comparative analysis with another approach that is generally not the standard of care in the same region was not feasible. This may explain the lack of this category of important studies from middle/northern Europe where at least partial staging was the standard (unlike the United States and southern Europe). The outcomes analyses from these studies supporting staging procedures are hindered by selection bias. Unfortunately, patient selection for adjuvant chemotherapy, which could represent a potential confounder, was not documented in most of these studies. However, in the 6 studies that reported on adjuvant treatment, a proportion of women who received chemotherapy was minimal, ranging from 0% to 13%. Median duration of follow-up was comparable among studies with conflicting conclusions. On analysis of individual staging steps, pelvic/paraaortic lymphadenectomy, peritoneal cytology, and peritoneal biopsy did not confer incremental survival benefit. Evidence for hysterectomy and omentectomy was sparse. However, unlike other steps, the prognostic value of omentectomy as a single step or in combination with other steps may warrant further evaluation. A recent review of the literature also reported that appendectomy, which is commonly conducted in women with mucinous low malignant potential, should be avoided in grossly normal appendices.64 Nevertheless, these findings are dependent on the final pathological diagnosis, given the limited accuracy of frozen sections (64%) and the probability of missing invasive cancer (9%).65 Not surprisingly, the current strategy for the establishment of guidelines
Systematic Reviews
ajog.org
TABLE 2
Clinical guidance and survey reports Type of information Country
Recommendation/ results
Year Source
Conclusion
These recommendations Full surgical are based on the ROBOT staging recommended study conducted in Germany
Guidelines/ International consensus (German predominance)
2014 Gynecologic Cancer InterGroup consensus
Guidelines/ United States consensus
2014 National Comprehensive NCCN disclaim aggressive Cancer Network (NCCN) procedure. There is no rule for omentectomy or lymphadenectomy.
Guidelines/ Canada consensus
2011 Cancer Care Ontario
Surgical staging does not This conclusion is based Classic surgical modify recurrence or on Wong et al,45 2007 staging is not mortality. study from Singapore indicated.
Survey
2009 5% from university clinics, 23% from tertiary care hospitals, 65% from secondary care hospitals, and 7% from general practitioners’ clinics.
Hysterectomy, 42% of the clinics; appendectomy, 35%; omentectomy, 62% of patients. Peritoneal biopsies, 94% of the university clinics; cytology, 92% of clinics; pelvic lymph node dissection, 18.9%
Classic surgical staging is prevalent among German surgeons.
Guidelines/ Australia consensus
2009 Greater Metropolitan Clinical Taskforce
Complete surgical staging None was cited is recommended (peritoneal cytology, exploration, biopsy of any suspicious lesions, omentectomy, peritoneal biopsies, and pelvic and para-aortic lymph node sampling)
Full surgical staging is recommended.
Guidelines/ United States consensus
2007 American College of Obstetricians and Gynecologists
Complete surgical staging None was cited is recommended (including hysterectomy with bilateral salpingooophorectomy)
Full surgical staging is recommended.
Survey
2000 Society of Gynecologic Oncologists
97% support surgical staging; 97% of them do omental sampling, 92% take random peritoneal biopsies, and 88% do lymph node sampling (89% paraaortic nodes and 97% pelvic nodes)
Classic surgical staging is adopted by most US surgeons.
Germany
United States
Complete surgical staging is recommended (midline laparotomy, cytology, resection of suspicious lesion, total hysterectomy and bilateral salpingooophorectomy, omentectomy, and peritoneal biopsies).
Main reference
Based on Wingo et. al56 Classic surgical (2002) and Winter et al55 staging is not indicated. (2006). Both were conducted in the United States
Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
reflected this regional trend as well. Among the 6 guidelines we included, 3 did not cite the studies from which they drew their recommendations about low
(continued)
malignant potential staging (2 did not recommend staging procedures vs 1 that supported staging).57,58,60 The other 3 guidelines cited only 1 or 2 studies,
mostly from the region that the guideline originated. One international consensus statement (mostly authors from Germany)
AUGUST 2016 American Journal of Obstetrics & Gynecology
165
Systematic Reviews
ajog.org
TABLE 2
Clinical guidance and survey reports (continued) Type of information Country
Recommendation/ results
Year Source
Main reference
Guidelines/ Canada consensus
2000 The Society of LMP tumors are staged None was cited Obstetricians and less aggressively than Gynaecologists of Canada invasive ovarian tumors; the tumor is completely resected, omental biopsy rather than omentectomy if the omentum is not involved, appendectomy for mucinous tumors only, and no lymph node resection or peritoneal biopsies. The uterus and the other ovary are preserved.
Survey
1999 Ovarian serous borderline tumors whose pathology slides were sent to the M. D. Anderson Cancer Center for second opinion consultation (between 1990 and 1996)
United States
Obstetriciangynecologists, gynecological oncologists, and general surgeons perform any staging biopsy in 65%, 95%, and 42%, respectively. Gynecological oncologists perform peritoneal/ omental sampling in 64% and along with lymph node sampling in 50% of cases.
Conclusion Classic surgical staging is not indicated.
Classic surgical staging is prevalent among US surgeons, namely gynecological oncologists.
LMP, low malignant potential. Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
cited a single German study that was published a year earlier as justification for recommending staging.59 The Canadian guidelines cited 1 Singaporean study that was published 4 years prior to the consensus statement,45 and the American guidelines issued in 2014 drew from 2 American studies that were published 8 and 12 years prior to the consensus guidelines.62 Therefore, it appears that current guidelines or consensus statements for or against staging procedures for low malignant potential do not reflect the robust available international data and hence exhibit strong regional predilection or preferences. Although this systematic review provides a thorough analysis of surgical staging in low malignant potential ovarian tumors, limitations exist. One limitation was that the pooled analysis of
data was not possible. A metaanalysis of Cox models that would have provided more precise estimates of differences in outcome measures was not feasible because actual data were not provided in many studies. Excluding these studies would have introduced bias in the analysis because they generally were not supportive of staging low malignant potential. Another concern is the heterogeneity of the term incomplete staging; this was not defined in most studies and it often included multiple staging elements. Thus, we plotted studies according to the actual steps they evaluated rather than commonly accepted definitions of surgical staging procedures.
strongly on the region of evidence. However, studies that evaluated surgical staging either in whole or by discrete or combined elements of staging lean heavily against performing staging procedures for low malignant potential ovarian tumors. To date, it would appear that there is no current evidence that surgical staging of low malignant potential ovarian tumors improves disease survival or recurrence, yet this practice continues in many regions of the world despite the surgical risks and increased cost. An international consensus guideline drawn from the best available evidence is needed to address this important clinical dilemma. REFERENCES
Conclusion In conclusion, the prognostic value of disease stage appears mixed and depends
166 American Journal of Obstetrics & Gynecology AUGUST 2016
1. Taylor HC. Malignant and semimalignant tumors of the ovary. Surg Gynecol Obstet 1929;48:204-30.
Systematic Reviews
ajog.org 2. Skírnisdóttir I, Garmo H, Wilander E, Holmberg L. Borderline ovarian tumors in Sweden 1960e2005: trends in incidence and age at diagnosis compared to ovarian cancer. Int J Cancer 2008;123:1897-901. 3. Sherman ME, Mink PJ, Curtis R, et al. Survival among women with borderline ovarian tumors and ovarian carcinoma. Cancer 2004;100:1045-52. 4. Fauvet R, Demblocque E, Morice P, Querleu D, Darai E. Behavior of serous borderline ovarian tumors with and without micropapillary patterns: results of a French multicenter study. Ann Surg Oncol 2012;19:941-7. 5. Quddus MR, Sung CJ, Zhang C, et al. The presence and location of epithelial implants and implants with epithelial proliferation may predict a higher risk of recurrence in serous borderline ovarian tumors: a clinicopathologic study of 188 cases. Hum Pathol 2012;43:747-52. 6. Yazbek J, Raju K, Ben-Nagi J, Holland T, Hillaby K, Jurkovic D. Accuracy of ultrasound subjective ‘pattern recognition’ for the diagnosis of borderline ovarian tumors. Ultrasound Obstet Gynecol 2007;29:489-95. 7. Gotlieb WH, Soriano D, Achiron R, et al. CA 125 measurement and ultrasonography in borderline tumors of the ovary. Am J Obstet Gynecol 2000;183:541-6. 8. Lin PS, Gershenson DM, Bevers MW, Lucas KR, Burke TW, Silva EG. The current status of surgical staging of ovarian serous borderline tumors. Cancer 1999;85:905-11. 9. Kærn J, Tropé CG, Abeler VM. A retrospective study of 370 borderline tumors of the ovary treated at the Norwegian Radium Hospital from 1970 to 1982. A review of clinicopathologic features and treatment modalities. Cancer 1993;71:1810-20. 10. Trimble CL, Kosary C, Trimble EL. Longterm survival and patterns of care in women with ovarian tumors of low malignant potential. Gynecol Oncol 2002;86:34-7. 11. Buttini M, Nicklin JL, Crandon A. Low malignant potential ovarian tumours: a review of 175 consecutive cases. Aust N Z J Obstet Gynaecol 1997;37:100-3. 12. Gorisek B, Stare MR, Arko D. Borderline tumors of the ovary—treatment and survival at maribor teaching hospital between 1993 and 2001. Zdravn Vestn 2009;78:463-6. 13. Sutton GP, Bundy BN, Omura GA, Yordan EL, Beecham JB, Bonfiglio T. Stage III ovarian tumors of low malignant potential treated with cisplatin combination therapy (a Gynecologic Oncology Group study). Gynecol Oncol 1991;41:230-3. 14. Menzin AW, Gal D, Lovecchio JL. Contemporary surgical management of borderline ovarian tumors: a survey of the Society of Gynecologic Oncologists. Gynecol Oncol 2000;78: 7-9. 15. Tinelli R, Tinelli A, Tinelli FG, Cicinelli E, Malvasi A. Conservative surgery for borderline ovarian tumors: a review. Gynecol Oncol 2006;100:185-91. 16. Trillsch F, Mahner S, Vettorazzi E, et al. Surgical staging and prognosis in serous
borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study. Br J Cancer 2015;112:660-6. 17. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013. Available at: http:// www.ohri.ca/programs/clinical_epidemiology/ oxford.asp. Accessed March 15, 2014. 18. du Bois A, Ewald-Riegler N, de Gregorio N, et al. Borderline tumours of the ovary: a cohort study of the Arbeitsgmeinschaft Gynäkologische Onkologie (AGO) Study Group. Eur JCancer 2013;49:1905-14. 19. Ewald-Riegler N, du Bois O, FisselerEckhoff A, et al. Borderline tumors of the ovary: clinical course and prognostic factors. Oncol Res Treat 2012;35:28-33. 20. Lenhard MS, Mitterer S, Kümper C, et al. Long-term follow-up after ovarian borderline tumor: relapse and survival in a large patient cohort. Eur J Obstet Gynecol Reprod Biol 2009;145:189-94. 21. Avril S, Hahn E, Specht K, et al. Histopathologic features of ovarian borderline tumors are not predictive of clinical outcome. Gynecol Oncol 2012;127:516-24. 22. Poncelet C, Fauvet R, Yazbeck C, Coutant C, Darai E. Impact of serum tumor marker determination on the management of women with borderline ovarian tumors: multivariate analysis of a French multicentre study. Eur J Surg Oncol 2010;36:1066-72. 23. Kane A, Uzan C, Rey A, et al. Prognostic factors in patients with ovarian serous low malignant potential (borderline) tumors with peritoneal implants. Oncologist 2009;14: 591-600. 24. Camatte S, Rouzier R, Boccara-Dekeyser J, et al. Pronostic et fertilité après traitement conservateur d’une tumeur ovarienne à la limite de la malignité: revue d’une série continue de 68 cas. Gynecol Obstet Fertil 2002;30: 583-91. 25. Azuar A, Bourdel N, Ferrarrese G, Dauplat J, Mage G, Canis M. Laparoscopic restaging of borderline ovarian tumours (BLOT): a retrospective study of 142 cases. Eur J Obstet Gynecol Reprod Biol 2013;168:87-91. 26. Koskas M, Uzan C, Gouy S, et al. Prognostic factors of a large retrospective series of mucinous borderline tumors of the ovary (excluding peritoneal pseudomyxoma). Ann Surg Oncol 2011;18:40-8. 27. Kristensen GS, Schledermann D, Mogensen O, Jochumsen KM. The value of random biopsies, omentectomy, and hysterectomy in operations for borderline ovarian tumors. Int J Gynecol Cancer 2014;24:874-9. 28. Loizzi V, Selvaggi L, Leone L, et al. Borderline epithelial tumors of the ovary: experience of 55 patients. Oncol Lett 2015;9:912-4. 29. Ferrero A, Strada I, Di Marcoberardino B, et al. Clinical significance of microinvasion in borderline ovarian tumors and its impact on surgical management. Int J Gynecol Cancer 2012;22:1158-62.
30. De Iaco P, Ferrero A, Rosati F, et al. Behaviour of ovarian tumors of low malignant potential treated with conservative surgery. Eur J Surg Oncol 2009;35:643-8. 31. Romagnolo C, Gadducci A, Sartori E, Zola P, Maggino T. Management of borderline ovarian tumors: results of an Italian multicenter study. Gynecol Oncol 2006;101:255-60. 32. Di Re F, Paladini D, Fontanelli R, Feudale E, Raspagliesi F. Surgical staging for epithelial ovarian tumors of low malignant potential. Int J Gynecol Cancer 1994;4:310-4. 33. Guvenal T, Dursun P, Hasdemir PS, et al. Effect of surgical staging on 539 patients with borderline ovarian tumors: a Turkish Gynecologic Oncology Group study. Gynecol Oncol 2013;131:546-50. 34. Baran SY, Goksedef BPC, Gorgen H, Çetin A. Retropective analysis of 25 cases with borderline ovarian tumors. J Turk Soc Obstet Gynecol 2011;8:107-12. 35. Pirimoglu ZM, Afsin Y, Guzelmeric K, Yilmaz M, Unal O, Turan MC. Is it necessary to do retroperitoneal evaluation in borderline epithelial ovarian tumors? Arch Gynecol Obstet 2008;277:411-4. 36. Ayhan A, Guven ESG, Guven S, Kucukali T. Recurrence and prognostic factors in borderline ovarian tumors. Gynecol Oncol 2005;98:439-45. 37. Cusidó M, Balagueró L, Hernandez G, et al. Results of the national survey of borderline ovarian tumors in Spain. Gynecol Oncol 2007;104:617-22. 38. Romeo M, Pons F, Barretina P, Radua J. Incomplete staging surgery as a major predictor of relapse of borderline ovarian tumor. World J Surg Oncol 2013;11:13. 39. Menczer J, Chetrit A, Sadetzki S. National Israel Ovarian Cancer Group. The effect of hysterectomy on survival of patients with borderline ovarian tumors. Gynecol Oncol 2012;125: 372-5. 40. Yokoyama Y, Moriya T, Takano T, et al. Clinical outcome and risk factors for recurrence in borderline ovarian tumours. Br J Cancer 2006;94:1586-91. 41. Tamakoshi K, Kikkawa F, Nakashima N, et al. Clinical behavior of borderline ovarian tumors: a study of 150 cases. J Surg Oncol 1997;64:147-52. 42. Park J-Y, Kim D-Y, Kim J-H, et al. Micropapillary pattern in serous borderline ovarian tumors: does it matter? Gynecol Oncol 2011;123:511-6. 43. Park J-Y, Kim D-Y, Kim J-H, Kim Y-M, Kim Y-T, Nam J-H. Surgical management of borderline ovarian tumors: the role of fertilitysparing surgery. Gynecol Oncol 2009;113: 75-82. 44. Ren J, Peng Z, Yang K. A clinicopathologic multivariate analysis affecting recurrence of borderline ovarian tumors. Gynecol Oncol 2008;110:162-7. 45. Wong H, Low J, Chua Y, Busmanis I, Tay E, Ho T. Ovarian tumors of borderline malignancy: a review of 247 patients from 1991 to 2004. Int J Gynecol Cancer 2007;17:342-9.
AUGUST 2016 American Journal of Obstetrics & Gynecology
167
Systematic Reviews 46. Tsai H-W, Ko C-C, Yeh C-C, et al. Unilateral salpingo-oophorectomy as fertility-sparing surgery for borderline ovarian tumors. J Chin Med Assoc 2011;74:250-4. 47. Tang A, Kondalsamy-Chennakesavan S, Ngan H, et al. Prognostic value of elevated preoperative serum CA125 in ovarian tumors of low malignant potential: a multinational collaborative study (ANZGOG0801). Gynecol Oncol 2012;126:36-40. 48. Sykes P, Quinn M, Rome R. Ovarian tumors of low malignant potential: a retrospective study of 234 patients. Int J Gynecol Cancer 1997;7:218-26. 49. Suh-Burgmann E. Long-term outcomes following conservative surgery for borderline tumor of the ovary: a large populationbased study. Gynecol Oncol 2006;103:841-7. 50. Gershenson DM, Silva EG, Levy L, Burke TW, Wolf JK, Tornos C. Ovarian serous borderline tumors with invasive peritoneal implants. Cancer 1998;82:1096-103. 51. Anfinan N, Sait K, Ghatage P, Nation J, Chu P. Ten years experience in the management of borderline ovarian tumors at Tom Baker Cancer Centre. Arch Gynecol Obstet 2011;284:731-5. 52. Leake JF, Currie JL, Rosenshein NB, Woodruff JD. Long-term follow-up of serous ovarian tumors of low malignant potential. Gynecol Oncol 1992;47:150-8.
ajog.org 53. Rao GG, Skinner E, Gehrig PA, Duska LR, Coleman RL, Schorge JO. Surgical staging of ovarian low malignant potential tumors. Obstet Gynecol 2004;104:261-6. 54. Shih K, Zhou Q, Huh J, et al. Risk factors for recurrence of ovarian borderline tumors. Gynecol Oncol 2011;120:480-4. 55. Winter WE, Kucera PR, Rodgers W, McBroom JW, Olsen C, Maxwell GL. Surgical staging in patients with ovarian tumors of low malignant potential. Obstet Gynecol 2002;100: 671-6. 56. Wingo SN, Knowles LM, Carrick KS, Miller DS, Schorge JO. Retrospective cohort study of surgical staging for ovarian low malignant potential tumors. Am J Obstet Gynecol 2006;194:e20-2. 57. American College of Obstetricians and Gynecologists. Management of adnexal masses. ACOG Practice bulletin. Obstet Gynecol 2007;110:201-4. 58. GMCT Gynaecological Oncology Guidelines Review Group. Best clinical practice gynaecological cancer guidelines. Sydney (Australia): New South Wales Department of Health; 2009. 59. Harter P, Gershenson D, Lhomme C, et al. Gynecologic Cancer InterGroup (GCIG) Consensus review for ovarian tumors of low malignant potential (borderline ovarian tumors). Int J Gynecol Cancer 2014;24:S5-8.
168 American Journal of Obstetrics & Gynecology AUGUST 2016
60. Ehlen T, Dubuc-Lissoir J, Heywood M. Management of low malignant potential tumour of the ovary. J Soc Obstet Gynaecol Can 2000;22:19-21. 61. Dodge J, Covens A, Lacchetti C, et al. Management of a suspicious adnexal mass. Program in Evidence-Based Care EvidenceBased Series No. 4-15. Presented at the Cancer Care Ontario, Toronto, Ontario, Canada, July 7, 2011. 62. Morgan R, Alvarez R, Armstrong D. NCCN clinical practice guidelines in oncology (NCCN Guidelines): ovarian cancer including fallopian tube cancer and primary peritoneal cancer. Available at: https://www.tri-kobe.org/nccn/ guideline/gynecological/english/ovarian.pdf. Accessed March 1, 2014. 63. Coumbos A, Sehouli J, Chekerov R, et al. Clinical management of borderline tumours of the ovary: results of a multicentre survey of 323 clinics in Germany. Br J Cancer 2009;100: 1731-8. 64. Kleppe M, Bruls J, Van Gorp T, et al. Mucinous borderline tumours of the ovary and the appendix: a retrospective study and overview of the literature. Gynecol Oncol 2014;133:155-8. 65. Song T, Choi CH, Kim H-J, et al. Accuracy of frozen section diagnosis of borderline ovarian tumors. Gynecol Oncol 2011;122:127-31.
ajog.org
Systematic Reviews
Appendix Study search strategy Ovid Database(s): EMBASE 1988 to 2015, week 13, Ovid MEDLINE(R) in process and other nonindexed citations and Ovid MEDLINE(R) 1946 to Present; EBM Reviews: Cochrane Central Register of Controlled Trials, February 2015; EBM Reviews: Cochrane Database of Systematic Reviews, 2005 to February 2015
n
Searches
1
exp Ovarian neoplasms/su [surgery]
2
([ovary or ovaries or ovarian or ovarial or ovarium] adj3 [cancer or neoplasm or neoplasia or tumor or tumor or teratoma or adenocarcinoma or carcinoma]) or brenner tumor or brenner tumor or dysgerminoma or endometrioid carcinoma or granulosa cell tumor or granulosa cell tumor or luteoma or Meigs syndrome or Sertoli-Leydig cell tumor or Sertoli-Leydig cell tumor or thecoma).mp.
3
su.fs.
3,125,985
4
surg.mp.
3,736,629
5
2 and (3 or 4)
50,877
6
1 or 5
51,277
7
([low or limited] and malignant and potential) or borderline).mp.
8
6 and 7
9
exp neoplasm staging
10
(Stage or staged or staging or TNM classification or TNM system or tumor node metastasis classification or tumor node metastasis system or tumor node metastasis classification or tumor node metastasis system or unstaged or unstaging).mp.
1,457,965
11
9 or 10
1,457,965
12
exp neoplasm recurrence, local
13
exp treatment outcome
1,809,689
14
exp prognosis
1,678,814
15
(Outcome or prognos or surviv or death or mortalit or morbidit or fatalit or progression or recidive or recrudescence or recurrence or recurrent or regeneration or relapse or relapsing).mp.
8,762,344
16
mo.fs.
17
12 or 13 or 14 or 15 or 16
18
8 and 11 and 17
1647
19
18 not (exp animals/not exp humans)
1584
20
Limit 19 to (editorial or erratum or letter or note or addresses or autobiography or bibliography or biography or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts [limit not valid in Embase, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process, CCTR, CDSR; records were retained])
21
19, not 20
22
From 18, keep 1585e1647
23
21 or 22
Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
Results 24,259 194,910
106,032 3614 306,521
124,419
451,349 8,902,881
14
1570 63 1633 (continued)
AUGUST 2016 American Journal of Obstetrics & Gynecology
168.e1
Systematic Reviews
ajog.org
(continued)
n
Searches
Results
24
Limit 23 to year, 1990 to current
1567
25
Remove duplicates from 24
1113
Scopus
1 Title-ABS-key ([ovary or ovaries or ovarian or ovarial or ovarium] W/3 [cancer or neoplasm or neoplasia or tumor or tumour or teratoma or adenocarcinoma or carcinoma]) or brenner tumor or brenner tumour or dysgerminoma or endometrioid carcinoma or granulosa cell tumor or granulosa cell tumour or luteoma or Meigs syndrome or Sertoli-Leydig cell tumor or Sertoli-Leydig cell tumour or thecoma) 2 Title-ABS-key (surg) 3 Title-ABS-key ([low or limited and malignan and potential] or borderline) 4 Title-ABS-key (stage or staged or staging or TNM classification or TNM system or tumor node metastasis classification or tumor node metastasis system or tumour node metastasis classification or tumour node metastasis system or unstaged or unstaging) 5 Title-ABS-key (outcome or prognos or surviv or death or mortalit or morbidit or fatalit or progression or recidive or recrudescence or recurrence or recurrent or regeneration or relapse or relapsing) 6 Pub year after 1989 7 1 and 2 and 3 and 4 and 5 and 6 8 Doc type (le) or doc type (ed) or doc type (bk) or doc type (er) or doc type (no) or doc type(sh) 9 7 and not 8 10 PMID (0) or PMID (1) or PMID (2) or PMID (3) or PMID (4) or PMID (5) or PMID (6) or PMID (7) or PMID (8) or PMID (9) 11 9 and not 10 ABS, abstract; bk, book; CCTR, Cochrane Central Register of Clinical Trials; CDSR, Cochrane Database of Systematic Reviews; ed, editorial; er, erratum; exp, explode; fs, floating subheadings; le, letter to the editor; mo.fs, first 2 letters of mortality; mp, multipurpose; no, note; sh, short survey; su.f, first 2 letters of surgery; surg, surgery; surg.mp, the first 4 letters of surgery; TNM, tumor node metastasis. Shazly. Staging of LMP ovarian tumors. Am J Obstet Gynecol 2016.
168.e2 American Journal of Obstetrics & Gynecology AUGUST 2016
