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Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review and meta-analysis
YGYNO-977789; No. of pages: 6; 4C: Gynecologic Oncology xxx (xxxx) xxx
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Review Article
Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review and meta-analysis Giorgio Bogani ⁎, Antonino Ditto, Salvatore Lopez, Francesca Bertolina, Ferdinando Murgia, Ciro Pinelli, Valentina Chiappa, Francesco Raspagliesi Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy
H I G H L I G H T S • • • •
Patients with stage IC OCCC experience good oncologic outcomes regardless the use of adjuvant chemotherapy. More than 70% of patients with OCCC have adjuvant chemotherapy. Adjuvant chemotherapy does not improve outcomes in stage IA and IB OCCC. Adjuvant chemotherapy improves overall survival in stage IC OCCC.
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Article history: Received 24 November 2019 Received in revised form 19 December 2019 Accepted 29 December 2019 Available online xxxx Keywords: Clear cell ovarian cancer Adjuvant chemotherapy Observation Recurrence Survival
a b s t r a c t The role of adjuvant chemotherapy in surgically staged stage I clear cell ovarian cancer (OCCC) is unclear. Here, we performed a systematic review and meta-analysis in order to evaluate the role of chemotherapy vs. observation in stage I OCCC. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; ID: #129628). A protocol was defined prior to the search include the population criteria, description of interventions, comparisons, and the outcomes of interest, according to the PRIMA guidelines. Overall, the study population included 5073 women. Stage I OCCC experienced a 5-year disease-free survival and a 5year overall survival of 83.7% and 86.9%, respectively. Pooled data suggested that in the overall population adjuvant chemotherapy did not impact on 5-year disease free survival (test for overall effect, Z = 0.18; p = 0.86) and 5-year overall survival (test for overall effect, Z = 0.62; p = 0.53). Focusing on 2264 stage IC OCCC we observed that adjuvant correlated with an improvement in overall survival (OR: 0.70 (95%CI: 0.52 to 0.93); Z = 2.44; p = 0.01). In conclusion our study underlines that adjuvant chemotherapy could be reserved for patients with stage IC OCCC; while in stage IA and IB it could be safely omitted. Owing to the inherent biases of the studies included in the meta-analysis further prospective evidences are needed. © 2020 Elsevier Inc. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . 2.1. Statistical analysis . . . . . . . . . . . . . . . 2.2. Methodological quality and risk of bias assessment 3. Results . . . . . . . . . . . . . . . . . . . . . . . 3.1. Evidence acquisition . . . . . . . . . . . . . . 3.2. Evidence synthesis . . . . . . . . . . . . . . . 3.3. Methodological quality and risk of bias assessment 4. Discussion . . . . . . . . . . . . . . . . . . . . . . Authors' contribution . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133 Milan, Italy. E-mail address: [email protected] (G. Bogani).
https://doi.org/10.1016/j.ygyno.2019.12.045 0090-8258/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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1. Introduction
2. Materials and methods
Ovarian cancer (OC) is one of the most common gynecologic cancers in developed countries, with an estimated N22,500 newly diagnosed cases and approximately 14,000 deaths for the year 2019 in the United States [1]. OC is considered one of the most lethal gynecological cancers due to the high proportion of cancer-specific death in comparison to its incidence [1]. OC should not be considered a single disease, but a group of heterogonous diseases. More than 9 out of 10 patients with OC are affected by epithelial cancer, arising from the epithelial surface of the ovary [2]. Other types of OC arise from germ or stromal cells of the ovary. The majority of epithelial OC are classified as high grade serous (accounting for 30–70%); while, less common types included: endometrioid (10–20%), mucinous (5–20%), clear cell (3–10%), and undifferentiated (1%) types [3–6]. Various histological types are related to different pathogenesis, natural history and prognosis [3–6]. In fact, 5year survival rates is estimated to be 20–35% for serous OC, 40–63% for endometrioid OC, 40–69% for mucinous OC, 35–50% for clear cell OC, and 11–29% for undifferentiated OC, respectively [4–6]. Ovarian clear cell carcinoma (OCCC) is a rare type and it is less prevalent among Western countries when compared to the Eastern one. It typically occurs at a younger age, it is diagnosed at an earlier stage of the disease, and often it is associated with endometriosis [7]. Survival outcomes are generally favorable in the early-stage stage of the disease, while, in the advanced stage are poorer than the high-grade serous counterpart [7]. Owing to the rarity of OCCC several features are still unclear. In particular, the role of adjuvant chemotherapy in surgically staged stage I OCCC is under debate. Few studies investigated pros and cons of adopting adjuvant chemotherapy in patients with OCCC [8–15], but the small sample size of most of these studies limited the generalization of their findings. Here, in the present paper we aimed to review the current evidence on the role of adjuvant chemotherapy in stage I OCCC and to perform a meta-analysis in order to assess the efficacy of chemotherapy in those patients.
This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; ID: #129628). A protocol was defined prior to the search including the population criteria, description of interventions, comparisons and the outcomes of interest. Our systematic review was done following the suggestions from the Preferred Reporting Items for Systematic Reviews and Metaexaminations (PRISMA) statement, during the processes of evidence acquisition and synthesis [16]. A systematical Literature search was performed using PubMed (MEDLINE), Web of Science and SCOPUS databases. The search was performed comprehensively, using several databases from each database's earliest inception to August 012019. We sought to identify all English language researches comparing different postoperative adjuvant strategies for patients diagnosed with early stage OCCC. We aimed to evaluate the role of adjuvant chemotherapy in patients affected by early stage OCCC, comparing outcomes of patients undergoing chemotherapy with those of patients undergoing observation only. For the process of evidence acquisition, Literature was queried using the following terms “clear cell ovarian cancer” OR “clear cell ovarian carcinoma” in combination with “adjuvant” or “chemotherapy”. References of included studies were hand searched in order to identify potentially relevant adjunctive papers. For each study, in case of available data, we extracted the following information: number of patients, baseline characteristics, data on treatments, 5-year disease-free survival and 5-year overall survival. Two independent reviewers (FM and FB) evaluated all studies in order to verify the inclusion criteria. Selection of studies was conducted on 2 levels of screening. First level screening; we screened titles and abstracts the following exclusion criteria: a) publications of case reports, letters, comments, and reviews not reporting original data; b) in vivo and/or in vitro studies; c) studies with fewer than 10 patients; and d) language other than English. Studies matching inclusion criteria were obtained in the complete form and reviewed in full-text version
Fig. 1. Study design.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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Table 1 Main characteristics of the included studies. Authors
Year of publication
Study design
Study period
Number of patients undergoing CHT
Number of patients undergoing OBS
Level of recommendation for GRADE system
Level of evidence for ACOG guidelines
Takano Mizuno Takada Shimizu Hogen Oseledchyk Nasioudis
2010 2012 2012 2015 2017 2017 2018
Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective
1992–2005 1991–2007 2000–2009 1995–2011 1995–2014 2000–2013 2004–2015
195 (89%) 91 (68.9%) 30 (41.1%) 152 (56.9%) 29 (48.3%) 1346 (67.5%) 1839 (79.1%)
24 (11%) 43 (32.1%) 43 (58.9%) 115 (43.1%) 31 (51.7%) 649 (32.5%) 486 (20.9%)
MQ MQ MQ MQ MQ MQ MQ
B B B B B B B
Abbreviation: GRADE = Grading of Recommendations, Assessment, Development, and Evaluation; ACOG = American College of Obstetricians and Gynecologists; LQ = low quality; MQ = medium quality; HQ = high quality; NR = not reported.
for an advance assessment. Second level screening included a full-text screening that was performed using the following inclusion criteria: a) original studies comparing adjuvant chemotherapy and observation in stage I OCCC, b) studies that include at least ten OCCC patients for each arm, and c) full text available in English. Differences of opinion were resolved by agreement between the reviewers.
respectively [18–21]. Details of GRADE and ACOG guidelines are reported elsewhere [19,20]. ACOG categorize quality and quantity of evidence, underlying recommendations, in three levels: level A (good and consistent evidence), level B (limited or inconsistent evidence) and level C (consensus and opinion) [18,19,21].
2.1. Statistical analysis
3.1. Evidence acquisition
Der-Simonian and Laird random-effects models were used to pool log transformed event rates and estimated 95% CI for dichotomous outcomes, and for continuous outcomes we calculated the weighted mean difference (MD) between the two interventions for each study and we pooled the effect size using the same models [17]. Across the included studies was measured the overall heterogeneity using I2 statistic, in which I2 N 50% suggests high heterogeneity [17]. 5-year disease-free survival was calculated on the basis of patients who were disease-free on the total with available information on disease status. 5-year overall survival was calculated on the basis of patients who were alive on the total with available information on vital status. The meta-analysis was performed using the Cochrane Review software (Review Manager version 5.3 for Mac).
Searching the Literature, we identified 1282 citations. Seven comparative series were selected after the exclusion of non-English language literature, single arm studies, duplicate publications, case series including b10 laparoscopic procedures, letters, editorials and reviews not reporting original data [8–13,15]. The process of evidence acquisition is detailed in Fig. 1. Included studies were summarized the in Table 1. Overall, 5073 patients were included: 3682 (72.5%) and 1391 (27.5%), having adjuvant chemotherapy and observation, respectively.
2.2. Methodological quality and risk of bias assessment Cochrane Collaboration's Risk of Bias assessment tool was used to assess the quality of randomization methods, allocation concealment, baseline imbalances, whether blinding was done adequately and who was blinded [17–19]. The quality and levels of recommendation of the investigations were assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) and American College of Obstetricians and Gynecologists guidelines (ACOG) guidelines,
3. Results
3.2. Evidence synthesis Overall, the study population included 5073 women, including 2264 stage IC OCCC. Table 2 shows characteristics of patients included in the studies. Stage I OCCC experienced a 5-year disease-free survival and a 5year overall survival of 83.7% and 86.9%, respectively. Table 3 shows oncologic outcomes of stage I OCC having chemotherapy and observation only. Polling together data we observed that various postoperative strategies (adjuvant chemotherapy vs. observation), did not impact on 5-year disease free survival (test for overall effect, Z = 0.18; p = 0.86) and 5year overall survival (test for overall effect, Z = 0.62; p = 0.53). Patients undergoing adjuvant chemotherapy experienced a 5-year disease free survival and 5-year overall survival of 83.3% and 88.4%, respectively.
Table 2 Disease characteristics. Authors
Year of publication
Therapeutic approach
FIGO stage IA/B
FIGO stage IC
FIGO grade 1
FIGO grade 2
FIGO grade 3
Cyst's rupture
Positive peritoneal cytology
Takano
2010
Mizuno
2012
Takada
2012
Shimizu
2015
Hogen
2017
Oseledchyk
2017
Nasioudis
2018
Chemotherapy (n = 195) No chemotherapy (n = 24) Chemotherapy (n = 91) No chemotherapy (n = 43) Chemotherapy (n = 30) No chemotherapy (n = 43) Chemotherapy (n = 152) No chemotherapy (n = 115) Chemotherapy (n = 29) No chemotherapy (n = 31) Chemotherapy (n = 1346) No chemotherapy (n = 649) Chemotherapy (n = 1839) No chemotherapy (n = 486)
77 (39.5%) 18 (75%) 16 (17.6%) 25 (58.1%) 4 (13.3%) 16 (37.2%) 19 (12.5%) 77 (66.9%) 12 (41.4%) 13 (41.9%) 759 (56.3%) 455 (70.1%) 980 (75.5%) 318 (24.5%)
118 (60.5%) 6 (25%) 75 (82.4%) 18 (41.9%) 26 (86.7%) 27 (62.8%) 133 (87.5%) 38 (33.1%) 17 (58.6%) 18 (58.1%) 587 (43.6%) 194 (29.9%) 847 (84.1%) 160 (15.9%)
NR NR NR NR NR NR NR NR NR NR NR NR NR NR
NR NR NR NR NR NR NR NR NR NR NR NR NR NR
NR NR NR NR NR NR NR NR NR NR NR NR NR NR
38 (19.5%) 4 (16.7%) 75 (82.4%) 18 (41.9%) 11 (36.7%) 16 (37.2%) 67 (44.1%) 34 (29.6%) NR NR NR NR NR NR
77 (39.5%) 2 (8.3%) // // NR NR 55 (36.2%) 4 (3.5%) 8 (27.6%) 1 (3.2%) NR NR NR NR
Abbreviations: FIGO, International Federation of Obstetrics and Gynecologists; N/R, not reported.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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Table 3 Oncologic outcomes. Authors
Year of publication
Therapeutic approach
Recurrence
Death of disease
Death for any cause
DFS at 5 yrs
OS at 5 yrs
Follow-up
Takano
2010
Mizuno
2012
Takada
2012
Shimizu
2015 2017
Oseledchyk
2017
Nasioudis
2018
35 (17.9%) 1 (4.2%) NR NR NR NR 20 (13.2%) 14 (12.2%) 6 (20.7%) 11 (35.5%) NR NR NR NR
NR NR NR NR NR NR NR NR 4 (13.8%) 7 (22.6%) NR NR NR NR
NR NR NR NR NR NR NR NR 5 (17.2%) 9 (29%) NR NR NR NR
77% 96% 88% 97.6% 80.1% 73.9% 88.9% 87.7% 86.2% 58.0% NR NR NR NR
86% 100% 91.3% 100% 87.4% 81.7% 92.9% 97.5% 92.8% 73.6% 85% 83% 89.2% 82.6%
48 (7–160) mo 43 (8–98) mo 64 (14–190) mo 60 (7–191) mo 30(14–113) mo 56(13–119) mo 65 (7–209) mo
Hogen
Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n
195) = 24) 91) = 43) 30) = 43) 152) = 115) 29) = 31) 1346) = 649) 1839) = 486)
6.21 yrs 3.18 yrs 64 mo 59.1 (1.1–151.4) mo 68.3 (1.7–151.8) mo
Abbreviations: DFS, disease-free survival; OS, overall survival; N/R, not reported; mo, months, yrs, years.
Patients having observation only experienced a 5-year disease free survival and 5-year overall survival of 84.4% and 84.7%, respectively. Forest plots showing the impact of adjuvant chemotherapy vs. observation in 5-year disease free and overall survivals are reported in Fig. 2. Since we observed that the prevalence of stage IC OCCC is higher among patients having adjuvant chemotherapy in comparison with observation (49% vs. 33.3%; p b 0.001, Fisher Exact Test), we restricted our analysis on stage IC OCCC (n = 2264), in order to reduce possible biases. This sub-analysis included 2264 patients: 1803 (79.6%) and 461 (20.4%), having adjuvant chemotherapy and observation, respectively. Supplemental Table 1 shows details of stage IC OCCC. Cumulative data on stage IC OCCC suggested that the administration of adjuvant chemotherapy is related to a slightly improvement in term of 5-year disease survival (69 recurrences out of 352 patients who had chemotherapy (19.6%) vs. 21 recurrences out of 89 patients who had observation (23.5%); OR: 0.77 (95%CI: 0.41 to 1.43); Z = 0.83; p = 0.41) and a statistically significant improvement in term of overall survival (224 deaths out of 1462 patients who had chemotherapy (15.3%)
vs. 80 recurrences out of 384 patients who had observation (20.8%); OR: 0.70 (95%CI: 0.52 to 0.93); Z = 2.44; p = 0.01). Fig. 3 shows forest plots on this association. 3.3. Methodological quality and risk of bias assessment All seven studies included were retrospective studies. The risk of allocation biases in the included studies was high for all seven studies. Overall, there was a relatively high heterogeneity (I2 N 50%) in term of survival outcomes among studies; while focusing on stage IC OCCC heterogeneity decreased. Detailed risk of bias assessment is described in Supplementary Fig. 1. 4. Discussion The present study reviewed the current evidence on the role of adjuvant chemotherapy in early-stage OCCC, thus reporting noteworthy findings. First, we reported pooled outcomes of a large series (N5000
Fig. 2. 5-year disease-free and overall survival in early-stage clear cells ovarian cancer.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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Fig. 3. 5-year disease-free and overall survival in stage IC clear cells ovarian cancer.
patients) of OCCC, observing a 5-year disease-free and overall survivals of 83.7% and 86.9%, respectively. Second, we observed that overall the adoption of adjuvant chemotherapy does not improve oncologic outcomes of stage I OCCC, and this is particularly true for patients diagnosed with stage IA and stage IB OCCC. Third, focusing on patients affected by stage IC OCCC, we observed that the administration of chemotherapy impacts in improving 5-year overall survival. International guidelines recommended the adoption of adjuvant chemotherapy in women diagnosed with ovarian cancer, regardless of stage at presentation and histological classification [22]. Moreover, several researches highlighted the need to perform adjuvant treatments in women with OCCC (even in the early stage), since patients with recurred OCCC experienced poor outcomes [8–13,15]. However, the estimated chemotherapy response rate ranges between 20 and 55% in patients with OCCC [8–13,15,20,21]. To date, the role of chemotherapy in early-stage OCCC is still controversial. Although some studies suggested that chemotherapy has a role in improving disease-free survival [11,15], other investigations suggested that the adoption of chemotherapy is not useful in OCCC [13]. Recently, Nasioudis et al., investigated patterns of use of adjuvant chemotherapy for stage I OCCC. The Authors performed an analysis of the National Cancer Database, evaluating a cohort of 2325 women treated for stage I OCCC between 2004 and 2015 [15]. The results of this studies highlighted that adjuvant chemotherapy is prescribed in about 8 out of 10 patients with stage I OCCC, highlighting the clinical need to address the question whether adjuvant chemotherapy is useful in those patients. As aforementioned, data on the efficacy of adjuvant chemotherapy are discordant. Nasioudis et al., observed that the administration of adjuvant chemotherapy statistically improves outcomes of stage IA and B OCCC (5-year overall survival: 92.5% vs. 84%; p b 0.001); while, this gain is less evident in patients with stage IC OCCC (5-year overall survival: 85.1% vs. 77.5%; p = 0.116) [15]. Oseledchyk et al. evaluated a cohort of 1995 women with stage IC OCCC included in the Surveillance,
Epidemiology, and End Results (SEER) database between 2000 and 2013 [13]. They observed that, of the 1374 (69%) patients who had chemotherapy, the 5-year overall survival rate was 85%, compared with 83% for those who had observation (p = 0.439). In patients with OCCC, there no significant effect of adjuvant chemotherapy on overall survival was observed, in any substage (stage IA/B and IC). Schimizu et al. reported data from the large multi-institutional retrospective study, including 267 patients (152 having adjuvant chemotherapy and 115 having observation). The author observed that overall chemotherapy has not influence in improving overall survivals in early stage ovarian cancer. While, it improves disease-free survival in stage IC OCCC [11]. Interestingly, an important aspect of performing a meta-analysis is to try to answer a broader question than those addressed by the primary studies it includes. The objective of the broader question is whether the administration of chemotherapy improves outcome in stage IC OCCC. There is a wide variation of the number of participants, characteristics of individuals involved (e.g., age, race), adjuvant chemotherapy details (e.g., number of cycles, agents, and dosage) and type of surgery (e.g., fully staged vs. unstaged, open vs. minimally invasive surgery). They are the most important biases of the present study. Hence, our results have to be considered purely exploratory. The main strengths of our review and meta-analysis is the systematic review process, the collection of a large number of patients with stage I OCCC and the execution of a meta-analysis focusing on 5-year oncologic results. Additionally, three main points of the present study have to be addressed. First, we observed that cumulative data on stage IC OCCC suggested that the administration of adjuvant chemotherapy is related to a slightly improvement in term of 5-year disease survival and a statistically significant improvement in term of overall survival. The rationale of these findings might be related to the number of patients included for the 5-year disease-free (n = 441) and overall (n = 1846) survivals analyses on the basis of the data available from the included studies.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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Second, in our meta-analysis the 5-year overall survival benefit largely depends on the results published by Nasioudis et al. [14]. However, we have to highlight that in the original paper, they failed to observe a clinical beneficial effect of adjuvant chemotherapy over a longer follow-up period (analysis at 140 months). Third, unfortunately, is was not possible to evaluate the impact of various stage IC sub-stages (i.e., IC1, IC2, IC3), because these data are not available in the included papers. We have to take in account that IC sub-stages might impact on patients prognosis and response to chemotherapy. In conclusion, the present investigation reviewed the current evidence on the role of adjuvant chemotherapy in stage I OCCC. Although OCCC is considered to be relative resistant to chemotherapy, more than seven out of ten patients had adjuvant chemotherapy. Patients diagnosed with stage IC OCCC are more likely to receive adjuvant chemotherapy in comparison to patients diagnosed with stage IA and IB OCCC. The administration of chemotherapy has not impact on stage I OCCC in term of 5-year disease-free and overall survivals. In patients with stage IC OCCC adjuvant chemotherapy seems to be associate with an improvement in term of 5-year overall survival. A large multiinstitutional prospective randomized trial would definitely ask the question whether adjuvant chemotherapy is useful in stage I OCCC. Innovative treatments, targeting specific genetic/molecular profile (i.e., the ARID1A gene) are warranted to improve outcomes of OCCC patients. Supplementary data to this article can be found online at https://doi. org/10.1016/j.ygyno.2019.12.045. Authors' contribution Conceptualization: GB and FR. Methodology: all authors. Data collection: all authors. Project administration: FR. Supervision: FR. Writing original draft: GB. Writing - review & editing: all authors. Declaration of competing interest The authors declare no conflicts of interest. No funding sources supported this investigation. References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2019, CA Cancer J. Clin. 69 (2019) 7–34. [2] D. Mysona, A. Pyrzak, S. Purohit, W. Zhi, A. Sharma, L. Tran, et al., A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer, Gynecol. Oncol. 152 (2019) 574–580. [3] L.C. Peres, K.L. Cushing-Haugen, M. Anglesio, K. Wicklund, R. Bentley, A. Berchuck, et al., Histotype classification of ovarian carcinoma: a comparison of approaches, Gynecol. Oncol. 151 (2018) 53–60. [4] A. Melamed, B. Manning-Geist, A.J. Bregar, E.J. Diver, A. Goodman, et al., Associations between residual disease and survival in epithelial ovarian cancer by histologic type, Gynecol. Oncol. 147 (2017) 250–256.
[5] K.E. Oliver, W.E. Brady, M. Birrer, D.M. Gershenson, G. Fleming, L.J. Copeland, et al., An evaluation of progression free survival and overall survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: an NRG Oncology/Gynecologic Oncology Group experience, Gynecol. Oncol. 147 (2017) 243–249. [6] E.M. Bednar, H.D. Oakley, C.C. Sun, C.C. Burke, M.F. Munsell, S.N. Westin, et al., A universal genetic testing initiative for patients with high-grade, non-mucinous epithelial ovarian cancer and the implications for cancer treatment, Gynecol. Oncol. 146 (2) (2017) 399–404Aug. [7] L. Hogen, D. Vicus, S.E. Ferguson, et al., Patterns of recurrence and impact on survival in patients with clear cell ovarian carcinoma, Int. J. Gynecol. Cancer 29 (2019) 1164–1169, https://doi.org/10.1136/ijgc-2019-000287. [8] M. Takano, T. Sugiyama, N. Yaegashi, S. Sagae, K. Kuzuya, Y. Udagawa, et al., Less impact of adjuvant chemotherapy for stage I clear cell carcinoma of the ovary: a retrospective Japan Clear Cell Carcinoma Study, Int. J. Gynecol. Cancer 20 (2010) 1506–1510. [9] M. Mizuno, H. Kajiyama, K. Shibata, K. Mizuno, O. Yamamuro, M. Kawai, et al., Adjuvant chemotherapy for stage i ovarian clear cell carcinoma: is it necessary for stage IA? Int. J. Gynecol. Cancer 22 (2012) 1143–1149. [10] T. Takada, H. Iwase, C. Iitsuka, H. Nomura, K. Sakamoto, K. Omatsu, et al., Adjuvant chemotherapy for stage I clear cell carcinoma of the ovary: an analysis of fully staged patients, Int. J. Gynecol. Cancer 22 (2012) 573–578. [11] D. Shimizu, N. Sato, T. Sato, K. Makino, M. Kito, H. Shirasawa, et al., Impact of adjuvant chemotherapy for stage I ovarian carcinoma with intraoperative tumor capsule rupture, J. Obstet. Gynaecol. Res. 41 (2015) 432–439. [12] L. Hogen, H. Brar, A. Covens, D. Bassiouny, M.Q. Bernardini, L.T. Gien, et al., Is adjuvant chemotherapy beneficial for surgical stage I ovarian clear cell carcinoma? Gynecol. Oncol. 147 (2017) 54–60, https://doi.org/10.1016/j.ygyno.2017.07.128. [13] A. Oseledchyk, M.M. Leitao Jr., J. Konner, R.E. O’Cearbhaill, D. Zamarin, Y. Sonoda, et al., Adjuvant chemotherapy in patients with stage I endometrioid or clear cell ovarian cancer in the platinum era: a surveillance, epidemiology, and end results cohort study, 2000–2013, Ann. Oncol. 28 (2017) 2985–2993. [14] D. Nasioudis, S.A. Mastroyannis, B.B. Albright, A.F. Haggerty, E.M. Ko, N.A. Latif, Adjuvant chemotherapy for stage I ovarian clear cell carcinoma: patterns of use and outcomes, Gynecol. Oncol. 150 (2018) 14–18, https://doi.org/10.1016/j.ygyno.2018.04. 567. [15] A. Liberati, D.G. Altman, J. Tetzlaff, C. Mulrow, P.C. Gøtzsche, J.P. Ioannidis, M. Clarke, P.J. Devereaux, J. Kleijnen, D. Moher, The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration, BMJ 339 (2009), b2700. [16] Bogani G, Fucà G, Maltese G, Ditto et al. Efficacy of adjuvant chemotherapy in early stage uterine leiomyosarcoma: a systematic review and meta-analysis. Gynecol. Oncol.. 2016;143:443–447. [17] J.J. Gagnier, The Cochrane risk of bias tool, Available at http://bmg.cochrane.org. [18] G.H. Guyatt, A.D. Oxman, G.E. Vist, R. Kunz, Y. Falck-Ytter, P. Alonso-Coello, et al., GRADE: an emerging consensus on rating quality of evidence and strength of recommendations, BMJ 336 (2008) 924–926. [19] J.D. Wright, N. Pawar, J.S. Gonzalez, S.N. Lewin, W.M. Burke, L.L. Simpson, et al., Scientific evidence underlying the American College of Obstetricians and Gynecologists’ practice bulletins, Obstet. Gynecol. 118 (2011) 505–512. [20] S.N. Westin, L. Randall, The European Society of Gynecologic Oncology (ESGO) 19th biannual meeting: overview and summary of selected topics, Gynecol. Oncol. 140 (2016) 377–380. [21] H.Y. Lee, J.H. Hong, J.H. Byun, H.J. Kim, S.K. Baek, J.Y. Kim, et al., Clinical characteristics of clear cell ovarian cancer: a retrospective multicenter experience of 308 patients in South Korea, Cancer Res. Treat. (2019) https://doi.org/10.4143/crt.2019. 292Jul 12. [22] G. Bogani, C. Borghi, U. Leone Roberti Maggiore, et al., Minimally invasive surgical staging in early-stage ovarian carcinoma: a systematic review and meta-analysis, J. Minim. Invasive Gynecol. 4 (2017) 552–562, https://doi.org/10.1016/j.jmig.2017. 02.013.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Review Article
Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review and meta-analysis Giorgio Bogani ⁎, Antonino Ditto, Salvatore Lopez, Francesca Bertolina, Ferdinando Murgia, Ciro Pinelli, Valentina Chiappa, Francesco Raspagliesi Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy
H I G H L I G H T S • • • •
Patients with stage IC OCCC experience good oncologic outcomes regardless the use of adjuvant chemotherapy. More than 70% of patients with OCCC have adjuvant chemotherapy. Adjuvant chemotherapy does not improve outcomes in stage IA and IB OCCC. Adjuvant chemotherapy improves overall survival in stage IC OCCC.
a r t i c l e
i n f o
Article history: Received 24 November 2019 Received in revised form 19 December 2019 Accepted 29 December 2019 Available online xxxx Keywords: Clear cell ovarian cancer Adjuvant chemotherapy Observation Recurrence Survival
a b s t r a c t The role of adjuvant chemotherapy in surgically staged stage I clear cell ovarian cancer (OCCC) is unclear. Here, we performed a systematic review and meta-analysis in order to evaluate the role of chemotherapy vs. observation in stage I OCCC. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; ID: #129628). A protocol was defined prior to the search include the population criteria, description of interventions, comparisons, and the outcomes of interest, according to the PRIMA guidelines. Overall, the study population included 5073 women. Stage I OCCC experienced a 5-year disease-free survival and a 5year overall survival of 83.7% and 86.9%, respectively. Pooled data suggested that in the overall population adjuvant chemotherapy did not impact on 5-year disease free survival (test for overall effect, Z = 0.18; p = 0.86) and 5-year overall survival (test for overall effect, Z = 0.62; p = 0.53). Focusing on 2264 stage IC OCCC we observed that adjuvant correlated with an improvement in overall survival (OR: 0.70 (95%CI: 0.52 to 0.93); Z = 2.44; p = 0.01). In conclusion our study underlines that adjuvant chemotherapy could be reserved for patients with stage IC OCCC; while in stage IA and IB it could be safely omitted. Owing to the inherent biases of the studies included in the meta-analysis further prospective evidences are needed. © 2020 Elsevier Inc. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . 2.1. Statistical analysis . . . . . . . . . . . . . . . 2.2. Methodological quality and risk of bias assessment 3. Results . . . . . . . . . . . . . . . . . . . . . . . 3.1. Evidence acquisition . . . . . . . . . . . . . . 3.2. Evidence synthesis . . . . . . . . . . . . . . . 3.3. Methodological quality and risk of bias assessment 4. Discussion . . . . . . . . . . . . . . . . . . . . . . Authors' contribution . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133 Milan, Italy. E-mail address: [email protected] (G. Bogani).
https://doi.org/10.1016/j.ygyno.2019.12.045 0090-8258/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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1. Introduction
2. Materials and methods
Ovarian cancer (OC) is one of the most common gynecologic cancers in developed countries, with an estimated N22,500 newly diagnosed cases and approximately 14,000 deaths for the year 2019 in the United States [1]. OC is considered one of the most lethal gynecological cancers due to the high proportion of cancer-specific death in comparison to its incidence [1]. OC should not be considered a single disease, but a group of heterogonous diseases. More than 9 out of 10 patients with OC are affected by epithelial cancer, arising from the epithelial surface of the ovary [2]. Other types of OC arise from germ or stromal cells of the ovary. The majority of epithelial OC are classified as high grade serous (accounting for 30–70%); while, less common types included: endometrioid (10–20%), mucinous (5–20%), clear cell (3–10%), and undifferentiated (1%) types [3–6]. Various histological types are related to different pathogenesis, natural history and prognosis [3–6]. In fact, 5year survival rates is estimated to be 20–35% for serous OC, 40–63% for endometrioid OC, 40–69% for mucinous OC, 35–50% for clear cell OC, and 11–29% for undifferentiated OC, respectively [4–6]. Ovarian clear cell carcinoma (OCCC) is a rare type and it is less prevalent among Western countries when compared to the Eastern one. It typically occurs at a younger age, it is diagnosed at an earlier stage of the disease, and often it is associated with endometriosis [7]. Survival outcomes are generally favorable in the early-stage stage of the disease, while, in the advanced stage are poorer than the high-grade serous counterpart [7]. Owing to the rarity of OCCC several features are still unclear. In particular, the role of adjuvant chemotherapy in surgically staged stage I OCCC is under debate. Few studies investigated pros and cons of adopting adjuvant chemotherapy in patients with OCCC [8–15], but the small sample size of most of these studies limited the generalization of their findings. Here, in the present paper we aimed to review the current evidence on the role of adjuvant chemotherapy in stage I OCCC and to perform a meta-analysis in order to assess the efficacy of chemotherapy in those patients.
This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; ID: #129628). A protocol was defined prior to the search including the population criteria, description of interventions, comparisons and the outcomes of interest. Our systematic review was done following the suggestions from the Preferred Reporting Items for Systematic Reviews and Metaexaminations (PRISMA) statement, during the processes of evidence acquisition and synthesis [16]. A systematical Literature search was performed using PubMed (MEDLINE), Web of Science and SCOPUS databases. The search was performed comprehensively, using several databases from each database's earliest inception to August 012019. We sought to identify all English language researches comparing different postoperative adjuvant strategies for patients diagnosed with early stage OCCC. We aimed to evaluate the role of adjuvant chemotherapy in patients affected by early stage OCCC, comparing outcomes of patients undergoing chemotherapy with those of patients undergoing observation only. For the process of evidence acquisition, Literature was queried using the following terms “clear cell ovarian cancer” OR “clear cell ovarian carcinoma” in combination with “adjuvant” or “chemotherapy”. References of included studies were hand searched in order to identify potentially relevant adjunctive papers. For each study, in case of available data, we extracted the following information: number of patients, baseline characteristics, data on treatments, 5-year disease-free survival and 5-year overall survival. Two independent reviewers (FM and FB) evaluated all studies in order to verify the inclusion criteria. Selection of studies was conducted on 2 levels of screening. First level screening; we screened titles and abstracts the following exclusion criteria: a) publications of case reports, letters, comments, and reviews not reporting original data; b) in vivo and/or in vitro studies; c) studies with fewer than 10 patients; and d) language other than English. Studies matching inclusion criteria were obtained in the complete form and reviewed in full-text version
Fig. 1. Study design.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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Table 1 Main characteristics of the included studies. Authors
Year of publication
Study design
Study period
Number of patients undergoing CHT
Number of patients undergoing OBS
Level of recommendation for GRADE system
Level of evidence for ACOG guidelines
Takano Mizuno Takada Shimizu Hogen Oseledchyk Nasioudis
2010 2012 2012 2015 2017 2017 2018
Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective
1992–2005 1991–2007 2000–2009 1995–2011 1995–2014 2000–2013 2004–2015
195 (89%) 91 (68.9%) 30 (41.1%) 152 (56.9%) 29 (48.3%) 1346 (67.5%) 1839 (79.1%)
24 (11%) 43 (32.1%) 43 (58.9%) 115 (43.1%) 31 (51.7%) 649 (32.5%) 486 (20.9%)
MQ MQ MQ MQ MQ MQ MQ
B B B B B B B
Abbreviation: GRADE = Grading of Recommendations, Assessment, Development, and Evaluation; ACOG = American College of Obstetricians and Gynecologists; LQ = low quality; MQ = medium quality; HQ = high quality; NR = not reported.
for an advance assessment. Second level screening included a full-text screening that was performed using the following inclusion criteria: a) original studies comparing adjuvant chemotherapy and observation in stage I OCCC, b) studies that include at least ten OCCC patients for each arm, and c) full text available in English. Differences of opinion were resolved by agreement between the reviewers.
respectively [18–21]. Details of GRADE and ACOG guidelines are reported elsewhere [19,20]. ACOG categorize quality and quantity of evidence, underlying recommendations, in three levels: level A (good and consistent evidence), level B (limited or inconsistent evidence) and level C (consensus and opinion) [18,19,21].
2.1. Statistical analysis
3.1. Evidence acquisition
Der-Simonian and Laird random-effects models were used to pool log transformed event rates and estimated 95% CI for dichotomous outcomes, and for continuous outcomes we calculated the weighted mean difference (MD) between the two interventions for each study and we pooled the effect size using the same models [17]. Across the included studies was measured the overall heterogeneity using I2 statistic, in which I2 N 50% suggests high heterogeneity [17]. 5-year disease-free survival was calculated on the basis of patients who were disease-free on the total with available information on disease status. 5-year overall survival was calculated on the basis of patients who were alive on the total with available information on vital status. The meta-analysis was performed using the Cochrane Review software (Review Manager version 5.3 for Mac).
Searching the Literature, we identified 1282 citations. Seven comparative series were selected after the exclusion of non-English language literature, single arm studies, duplicate publications, case series including b10 laparoscopic procedures, letters, editorials and reviews not reporting original data [8–13,15]. The process of evidence acquisition is detailed in Fig. 1. Included studies were summarized the in Table 1. Overall, 5073 patients were included: 3682 (72.5%) and 1391 (27.5%), having adjuvant chemotherapy and observation, respectively.
2.2. Methodological quality and risk of bias assessment Cochrane Collaboration's Risk of Bias assessment tool was used to assess the quality of randomization methods, allocation concealment, baseline imbalances, whether blinding was done adequately and who was blinded [17–19]. The quality and levels of recommendation of the investigations were assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) and American College of Obstetricians and Gynecologists guidelines (ACOG) guidelines,
3. Results
3.2. Evidence synthesis Overall, the study population included 5073 women, including 2264 stage IC OCCC. Table 2 shows characteristics of patients included in the studies. Stage I OCCC experienced a 5-year disease-free survival and a 5year overall survival of 83.7% and 86.9%, respectively. Table 3 shows oncologic outcomes of stage I OCC having chemotherapy and observation only. Polling together data we observed that various postoperative strategies (adjuvant chemotherapy vs. observation), did not impact on 5-year disease free survival (test for overall effect, Z = 0.18; p = 0.86) and 5year overall survival (test for overall effect, Z = 0.62; p = 0.53). Patients undergoing adjuvant chemotherapy experienced a 5-year disease free survival and 5-year overall survival of 83.3% and 88.4%, respectively.
Table 2 Disease characteristics. Authors
Year of publication
Therapeutic approach
FIGO stage IA/B
FIGO stage IC
FIGO grade 1
FIGO grade 2
FIGO grade 3
Cyst's rupture
Positive peritoneal cytology
Takano
2010
Mizuno
2012
Takada
2012
Shimizu
2015
Hogen
2017
Oseledchyk
2017
Nasioudis
2018
Chemotherapy (n = 195) No chemotherapy (n = 24) Chemotherapy (n = 91) No chemotherapy (n = 43) Chemotherapy (n = 30) No chemotherapy (n = 43) Chemotherapy (n = 152) No chemotherapy (n = 115) Chemotherapy (n = 29) No chemotherapy (n = 31) Chemotherapy (n = 1346) No chemotherapy (n = 649) Chemotherapy (n = 1839) No chemotherapy (n = 486)
77 (39.5%) 18 (75%) 16 (17.6%) 25 (58.1%) 4 (13.3%) 16 (37.2%) 19 (12.5%) 77 (66.9%) 12 (41.4%) 13 (41.9%) 759 (56.3%) 455 (70.1%) 980 (75.5%) 318 (24.5%)
118 (60.5%) 6 (25%) 75 (82.4%) 18 (41.9%) 26 (86.7%) 27 (62.8%) 133 (87.5%) 38 (33.1%) 17 (58.6%) 18 (58.1%) 587 (43.6%) 194 (29.9%) 847 (84.1%) 160 (15.9%)
NR NR NR NR NR NR NR NR NR NR NR NR NR NR
NR NR NR NR NR NR NR NR NR NR NR NR NR NR
NR NR NR NR NR NR NR NR NR NR NR NR NR NR
38 (19.5%) 4 (16.7%) 75 (82.4%) 18 (41.9%) 11 (36.7%) 16 (37.2%) 67 (44.1%) 34 (29.6%) NR NR NR NR NR NR
77 (39.5%) 2 (8.3%) // // NR NR 55 (36.2%) 4 (3.5%) 8 (27.6%) 1 (3.2%) NR NR NR NR
Abbreviations: FIGO, International Federation of Obstetrics and Gynecologists; N/R, not reported.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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Table 3 Oncologic outcomes. Authors
Year of publication
Therapeutic approach
Recurrence
Death of disease
Death for any cause
DFS at 5 yrs
OS at 5 yrs
Follow-up
Takano
2010
Mizuno
2012
Takada
2012
Shimizu
2015 2017
Oseledchyk
2017
Nasioudis
2018
35 (17.9%) 1 (4.2%) NR NR NR NR 20 (13.2%) 14 (12.2%) 6 (20.7%) 11 (35.5%) NR NR NR NR
NR NR NR NR NR NR NR NR 4 (13.8%) 7 (22.6%) NR NR NR NR
NR NR NR NR NR NR NR NR 5 (17.2%) 9 (29%) NR NR NR NR
77% 96% 88% 97.6% 80.1% 73.9% 88.9% 87.7% 86.2% 58.0% NR NR NR NR
86% 100% 91.3% 100% 87.4% 81.7% 92.9% 97.5% 92.8% 73.6% 85% 83% 89.2% 82.6%
48 (7–160) mo 43 (8–98) mo 64 (14–190) mo 60 (7–191) mo 30(14–113) mo 56(13–119) mo 65 (7–209) mo
Hogen
Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n Chemotherapy (n = No chemotherapy (n
195) = 24) 91) = 43) 30) = 43) 152) = 115) 29) = 31) 1346) = 649) 1839) = 486)
6.21 yrs 3.18 yrs 64 mo 59.1 (1.1–151.4) mo 68.3 (1.7–151.8) mo
Abbreviations: DFS, disease-free survival; OS, overall survival; N/R, not reported; mo, months, yrs, years.
Patients having observation only experienced a 5-year disease free survival and 5-year overall survival of 84.4% and 84.7%, respectively. Forest plots showing the impact of adjuvant chemotherapy vs. observation in 5-year disease free and overall survivals are reported in Fig. 2. Since we observed that the prevalence of stage IC OCCC is higher among patients having adjuvant chemotherapy in comparison with observation (49% vs. 33.3%; p b 0.001, Fisher Exact Test), we restricted our analysis on stage IC OCCC (n = 2264), in order to reduce possible biases. This sub-analysis included 2264 patients: 1803 (79.6%) and 461 (20.4%), having adjuvant chemotherapy and observation, respectively. Supplemental Table 1 shows details of stage IC OCCC. Cumulative data on stage IC OCCC suggested that the administration of adjuvant chemotherapy is related to a slightly improvement in term of 5-year disease survival (69 recurrences out of 352 patients who had chemotherapy (19.6%) vs. 21 recurrences out of 89 patients who had observation (23.5%); OR: 0.77 (95%CI: 0.41 to 1.43); Z = 0.83; p = 0.41) and a statistically significant improvement in term of overall survival (224 deaths out of 1462 patients who had chemotherapy (15.3%)
vs. 80 recurrences out of 384 patients who had observation (20.8%); OR: 0.70 (95%CI: 0.52 to 0.93); Z = 2.44; p = 0.01). Fig. 3 shows forest plots on this association. 3.3. Methodological quality and risk of bias assessment All seven studies included were retrospective studies. The risk of allocation biases in the included studies was high for all seven studies. Overall, there was a relatively high heterogeneity (I2 N 50%) in term of survival outcomes among studies; while focusing on stage IC OCCC heterogeneity decreased. Detailed risk of bias assessment is described in Supplementary Fig. 1. 4. Discussion The present study reviewed the current evidence on the role of adjuvant chemotherapy in early-stage OCCC, thus reporting noteworthy findings. First, we reported pooled outcomes of a large series (N5000
Fig. 2. 5-year disease-free and overall survival in early-stage clear cells ovarian cancer.
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Fig. 3. 5-year disease-free and overall survival in stage IC clear cells ovarian cancer.
patients) of OCCC, observing a 5-year disease-free and overall survivals of 83.7% and 86.9%, respectively. Second, we observed that overall the adoption of adjuvant chemotherapy does not improve oncologic outcomes of stage I OCCC, and this is particularly true for patients diagnosed with stage IA and stage IB OCCC. Third, focusing on patients affected by stage IC OCCC, we observed that the administration of chemotherapy impacts in improving 5-year overall survival. International guidelines recommended the adoption of adjuvant chemotherapy in women diagnosed with ovarian cancer, regardless of stage at presentation and histological classification [22]. Moreover, several researches highlighted the need to perform adjuvant treatments in women with OCCC (even in the early stage), since patients with recurred OCCC experienced poor outcomes [8–13,15]. However, the estimated chemotherapy response rate ranges between 20 and 55% in patients with OCCC [8–13,15,20,21]. To date, the role of chemotherapy in early-stage OCCC is still controversial. Although some studies suggested that chemotherapy has a role in improving disease-free survival [11,15], other investigations suggested that the adoption of chemotherapy is not useful in OCCC [13]. Recently, Nasioudis et al., investigated patterns of use of adjuvant chemotherapy for stage I OCCC. The Authors performed an analysis of the National Cancer Database, evaluating a cohort of 2325 women treated for stage I OCCC between 2004 and 2015 [15]. The results of this studies highlighted that adjuvant chemotherapy is prescribed in about 8 out of 10 patients with stage I OCCC, highlighting the clinical need to address the question whether adjuvant chemotherapy is useful in those patients. As aforementioned, data on the efficacy of adjuvant chemotherapy are discordant. Nasioudis et al., observed that the administration of adjuvant chemotherapy statistically improves outcomes of stage IA and B OCCC (5-year overall survival: 92.5% vs. 84%; p b 0.001); while, this gain is less evident in patients with stage IC OCCC (5-year overall survival: 85.1% vs. 77.5%; p = 0.116) [15]. Oseledchyk et al. evaluated a cohort of 1995 women with stage IC OCCC included in the Surveillance,
Epidemiology, and End Results (SEER) database between 2000 and 2013 [13]. They observed that, of the 1374 (69%) patients who had chemotherapy, the 5-year overall survival rate was 85%, compared with 83% for those who had observation (p = 0.439). In patients with OCCC, there no significant effect of adjuvant chemotherapy on overall survival was observed, in any substage (stage IA/B and IC). Schimizu et al. reported data from the large multi-institutional retrospective study, including 267 patients (152 having adjuvant chemotherapy and 115 having observation). The author observed that overall chemotherapy has not influence in improving overall survivals in early stage ovarian cancer. While, it improves disease-free survival in stage IC OCCC [11]. Interestingly, an important aspect of performing a meta-analysis is to try to answer a broader question than those addressed by the primary studies it includes. The objective of the broader question is whether the administration of chemotherapy improves outcome in stage IC OCCC. There is a wide variation of the number of participants, characteristics of individuals involved (e.g., age, race), adjuvant chemotherapy details (e.g., number of cycles, agents, and dosage) and type of surgery (e.g., fully staged vs. unstaged, open vs. minimally invasive surgery). They are the most important biases of the present study. Hence, our results have to be considered purely exploratory. The main strengths of our review and meta-analysis is the systematic review process, the collection of a large number of patients with stage I OCCC and the execution of a meta-analysis focusing on 5-year oncologic results. Additionally, three main points of the present study have to be addressed. First, we observed that cumulative data on stage IC OCCC suggested that the administration of adjuvant chemotherapy is related to a slightly improvement in term of 5-year disease survival and a statistically significant improvement in term of overall survival. The rationale of these findings might be related to the number of patients included for the 5-year disease-free (n = 441) and overall (n = 1846) survivals analyses on the basis of the data available from the included studies.
Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045
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G. Bogani et al. / Gynecologic Oncology xxx (xxxx) xxx
Second, in our meta-analysis the 5-year overall survival benefit largely depends on the results published by Nasioudis et al. [14]. However, we have to highlight that in the original paper, they failed to observe a clinical beneficial effect of adjuvant chemotherapy over a longer follow-up period (analysis at 140 months). Third, unfortunately, is was not possible to evaluate the impact of various stage IC sub-stages (i.e., IC1, IC2, IC3), because these data are not available in the included papers. We have to take in account that IC sub-stages might impact on patients prognosis and response to chemotherapy. In conclusion, the present investigation reviewed the current evidence on the role of adjuvant chemotherapy in stage I OCCC. Although OCCC is considered to be relative resistant to chemotherapy, more than seven out of ten patients had adjuvant chemotherapy. Patients diagnosed with stage IC OCCC are more likely to receive adjuvant chemotherapy in comparison to patients diagnosed with stage IA and IB OCCC. The administration of chemotherapy has not impact on stage I OCCC in term of 5-year disease-free and overall survivals. In patients with stage IC OCCC adjuvant chemotherapy seems to be associate with an improvement in term of 5-year overall survival. A large multiinstitutional prospective randomized trial would definitely ask the question whether adjuvant chemotherapy is useful in stage I OCCC. Innovative treatments, targeting specific genetic/molecular profile (i.e., the ARID1A gene) are warranted to improve outcomes of OCCC patients. Supplementary data to this article can be found online at https://doi. org/10.1016/j.ygyno.2019.12.045. Authors' contribution Conceptualization: GB and FR. Methodology: all authors. Data collection: all authors. Project administration: FR. Supervision: FR. Writing original draft: GB. Writing - review & editing: all authors. Declaration of competing interest The authors declare no conflicts of interest. No funding sources supported this investigation. References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2019, CA Cancer J. Clin. 69 (2019) 7–34. [2] D. Mysona, A. Pyrzak, S. Purohit, W. Zhi, A. Sharma, L. Tran, et al., A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer, Gynecol. Oncol. 152 (2019) 574–580. [3] L.C. Peres, K.L. Cushing-Haugen, M. Anglesio, K. Wicklund, R. Bentley, A. Berchuck, et al., Histotype classification of ovarian carcinoma: a comparison of approaches, Gynecol. Oncol. 151 (2018) 53–60. [4] A. Melamed, B. Manning-Geist, A.J. Bregar, E.J. Diver, A. Goodman, et al., Associations between residual disease and survival in epithelial ovarian cancer by histologic type, Gynecol. Oncol. 147 (2017) 250–256.
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Please cite this article as: G. Bogani, A. Ditto, S. Lopez, et al., Adjuvant chemotherapy vs. observation in stage I clear cell ovarian carcinoma: A systematic review a..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.045