Open Access, Peer-reviewed
pISSN 2005-0380   eISSN 2005-0399
    J Gynecol Oncol. 2023 Nov;34(6):e82. English.
    Published online Sep 05, 2023.
    https://doi.org/10.3802/jgo.2023.34.e82
    © 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology
    Original Article

    Optimal number of neoadjuvant chemotherapy cycles prior to interval debulking surgery in advanced epithelial ovarian cancer: a systematic review and meta-analysis of progression-free survival and overall survival

    Camelia Alexandra Coada,1,* Giulia Dondi,1,2,* Gloria Ravegnini,3,* Stella Di Costanzo,2 Marco Tesei,2 Enrico Fiuzzi,1,2 Marco Di Stanislao,1,2 Susanna Giunchi,2 Claudio Zamagni,4 Alessandro Bovicelli,1 Patrizia Hrelia,3 Sabrina Angelini,3 Pierandrea De Iaco,1,2 and Anna Myriam Perrone1,2
      • 1Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
      • 2Division of Oncologic Gynecology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
      • 3Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
      • 4Addarii Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
    • Correspondence to Stella Di Costanzo. Division of Oncologic Gynecology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, via Massarenti 9, 40138 Bologna, Italy. Email: stella.dicostanzo@aosp.bo.it

      *Camelia Alexandra Coada, Giulia Dondi, and Gloria Ravegnini contributed equally to this work as contributors.
    Received February 11, 2023; Revised May 31, 2023; Accepted June 24, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Objective

    Neoadjuvant chemotherapy (NACT) represents a treatment option in patients with advanced epithelial ovarian cancer (AEOC) who are not good candidates for primary debulking surgery. Usually, 3 cycles of chemotherapy before surgery have been considered the best option for patient survival, although quite often some patients receive more than 3 cycles. The aim of this systematic review and meta-analysis was to identify the optimal number of NACT cycles reporting better survival in AEOC patients.

    Methods

    PubMed, Cochrane Library, and Scopus were searched for original articles that analyzed the relationship between the number of chemotherapy cycles and clinical outcomes in AEOC patients before interval debulking surgery (IDS). The main outcomes were progression-free survival (PFS) and overall survival (OS).

    Results

    A total of 22 studies comprising 7,005 patients diagnosed with AEOC were included in our analysis. In terms of survival, the reviewed studies dividing the patients in ≤3 NACT cycles vs. >3, showed a trend for a decrease in PFS and a significant reduction in OS with an increasing number of cycles, while a difference in both PFS and OS was revealed if early IDS included patients with 4 NACT cycles. These results should be interpreted with caution due to the complex characteristics of AEOC patients.

    Conclusion

    In conclusion, our review and meta-analysis revealed that there is not enough evidence to determine the optimal number of NACT treatments before surgery. Further research in the form of well-designed randomized controlled trials is necessary to address this issue.

    Trial Registration

    PROSPERO Identifier: CRD42022334959

    Graphical Abstract

    Keywords
    Neoadjuvant Chemotherapy; Prognosis; Ovarian Cancer; Cytoreductive Surgery; Survival

    INTRODUCTION

    Epithelial ovarian cancer (EOC) is a rare but deadly disease [1]. Primary debulking surgery (PDS) associated to platinum-based chemotherapy represents the preferred therapy. Over the years, increased surgical aggressiveness led to improved survival, assuming that even the removal of extra-abdominal metastases could be performed with the aim of pursuing the absence of residual disease post-surgery [2, 3]. However, in cases where PDS with optimal residual disease is not feasible, or in unfit patients, shrinkage of the disease through neoadjuvant chemotherapy (NACT) is attempted, followed by interval debulking surgery (IDS) [4]. The number of NACT cycles has been arbitrarily set at 3, due to the Chorus and EORTC 55971 trials that compared PDS and IDS performed after 3 NACT cycles [5, 6]. The concept of performing surgery with the minimum number of cycles before IDS was also reaffirmed by a complex analysis by Bristow and Chi [7], who calculated a reduced survival of 4.1 months for each additional cycle of NACT. Currently, even though the optimal number of NACT cycles before IDS is not clearly defined, the international guidelines suggest 3–4 cycles, while in clinical practice the attitude seems to be 6 cycles prior IDS [8]. Generally, IDS is performed either early or delayed. Early IDS is conducted after 3 cycles in patients who are responding well to treatment or in high-volume medical centers. Delayed IDS, on the other hand, is performed after 5 or 6 cycles in slow-responding or unfit patients, or in low-volume medical centers.

    The definition of the optimal number of cycles is extraordinarily complex, and around the world the treatment of ovarian cancer varies according to the availability of both medical expertise and economic resources linked to the patient’s area of residence. Thus, the number of NACT cycles appears to be associated with both the disease response as well as with the availability of medical facilities and, therefore, a substantial proportion of women may not receive IDS. Reasons for not undergoing surgery may include poor response to NACT, death during treatment, coexisting medical conditions, frailty, and patient preference [9].

    For the reasons listed above and given the multitude of studies in the literature on this topic, we attempted to group the results of studies that examined the relationship between prognosis and number of NACT cycles in patients undergoing IDS. Our study aims to provide clinicians with a clearer understanding of the optimal number of chemotherapy cycles in the management of ovarian cancer prior to IDS.

    MATERIALS AND METHODS

    1. Articles selection

    This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) principles [10] and aimed to answer the research question: “What is the optimal number of NACT cycles for the best survival outcomes in advanced epithelial ovarian cancer (AEOC) patients before IDS?” The study protocol was registered in the PROSPERO on June 4, 2022 (CRD42022334959).

    The databases PubMed, Cochrane Library, and Scopus were searched for original articles that analyzed the relationship between the number of chemotherapy cycles and clinical outcomes in AEOC patients before IDS. The search was last updated on November 14, 2022. Relevant studies were selected using the Boolean combination of the following key terms: “neoadjuvant therapy” OR “neoadjuvant chemotherapy” OR “NACT” OR “NAC” and “treatment outcome” OR “treatment result” OR “treatment consequence” AND “ovarian cancer” OR “ovarian carcinoma” OR “ovarian neoplasm”. A professional librarian conducted the construction of the search string, database queries, and results.

    The population included AEOC patients treated with various numbers of NACT cycles before IDS. The main outcomes were progression-free survival (PFS) and overall survival (OS).

    2. Inclusion criteria and study selection

    Studies were included if they met the following criteria: 1) patients treated with standard NACT and IDS for AEOC; 2) AEOC stages International Federation of Gynecology and Obstetrics (FIGO) III–IV; 3) at least 2 years of survival and/or progression data; 4) comparison between number of NACT cycles and patients’ outcomes (PFS, OS); 5) randomized controlled trials (RCTs), observational prospective and retrospective studies; 6) English language.

    Exclusion criteria were: 1) studies conducted on other types of ovarian cancers (i.e., non-epithelial); 2) abstracts, editorials, letters, comments to editors, systematic and narrative reviews, meta-analyses without any new patient data, book chapters and case reports.

    Three authors independently screened titles and abstracts of articles (G.D., G.R. and C.A.C.). Articles were loaded into the Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia. Available at www.covidence.org) to eliminate duplicates and begin the reviewing process. Studies that failed to meet inclusion criteria were discarded. Full-text articles were independently assessed, and disputes were settled through consultation with a senior author (A.M.P.). The review results were discussed among all authors for interdisciplinary issues. Afterwards, data from each eligible study were extracted and tabulated. Quality assessment was performed using a National Institutes of Health developed Quality Assessment tool for Observational Cohort and Cross-Sectional Studies following their guidelines (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools). Quality Rating was done for each point using the following scale: good (11–14 out of 14 questions), fair (5–10 out of 14 questions), or poor (0–4 out of 14 questions), and reported in the quality assessment table.

    3. Statistical analysis and meta-analysis

    Descriptive statistics were presented as number and frequency for categorical variables while mean and standard deviation or median and range for continuous variables. Significance in the distribution of categorical variables was tested using the χ2 test. Meta-analysis of PFS and OS data was done using the meta package in R (R Foundation for Statistical Computing, Vienna, Austria). When authors performed the hazard analysis, the reported values were inserted into the pooled analysis. However, in case of absence of such data, indirect estimation was performed by extracting the time-to-event data from the Kaplan-Meier curves provided in each paper. Graphical points were obtained by manual digitalization using ScanIt Software by AmsterCHEM (https://www.amsterchem.com/scanit.html) and the curves were reconstructed using the KMtoIPD R package [11]. Hazard ratios (HRs) were estimated using the resulting patients summary statistics [12]. A p-value of 0.05 was established as the threshold for significance. The study heterogeneity was quantified using Tau2, Cochran’s Q and the Higgins & Thompson’s I2 statistic. Tau2 >0.1 and a 95% confidence interval (CI) not including 0 were considered to indicate substantial heterogeneity. I2 values above 40% were considered to represent moderate heterogeneity while values above 75% were considered an indication of considerable heterogeneity. The presence of substantial between-study heterogeneity was considered for a p<0.1. Outlier analysis was performed and studies with CIs not overlapping with the pooled CIs were considered potential outliers. Funnel plots were used to inspect publication bias while Egger’s regression test was used to test for asymmetry in the funnel plot.

    RESULTS

    1. Description of the included studies

    The results of the literature research are shown in the PRISMA flowchart (Fig. 1). After removing duplicates, 1,497 studies were selected for title and abstract screening, with 1,156 being removed due to irrelevance toward the topic under investigation. An additional 341 full text articles were evaluated, but 319 were excluded due to a lack of correlation between survival outcomes and number of NACT cycles or no reporting of the number of NACT cycles (Fig. 1). Finally, 22 articles met the inclusion criteria and were analyzed in the systematic review (Table 1).

    Fig. 1
    Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart showing the selection of studies for the systematic review and meta-analysis and the stepwise exclusion.
    AEOC, advanced epithelial ovarian cancer; IDS, interval debulking surgery; IP, intraperitoneal; NACT, neoadjuvant chemotherapy; OS, overall survival; PFS, progression-free survival.

    Table 1
    Summary of the studies included in the meta-analysis

    Most of the included studies were conducted in Europe (12 studies; 54.5%), followed by North America (4 studies; 18.2%), Asia (5 studies; 22.7%) and Australia (1 study; 4.5%). In terms of study design, one was prospective, while the other 21 were retrospective, 4 were multicenter, and 18 were single center. The enrollment period was estimated to be around 20 years, from 1980 to 2020, and the studies were published between 2009 and 2022, with 45.5% in the last 3 years (Fig. S1A). Funnel plots of the studies showed a symmetric distribution and the Egger’s test indicated the lack of funnel plot asymmetry suggesting the absence of publication biases both in case of PFS as well as OS (Fig. S1B).

    The primary objective of 15 studies was the investigation of PFS and OS with respect to the number of NACT cycles [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27], while in the remaining studies this result was reported but not as the primary outcome [28, 29, 30, 31, 32, 33].

    The NACT regimens reported in 18 studies were 3-weekly or weekly administration of platinum and taxane, while 3 studies did not specify the regimens [15, 17, 21]. One study reported the administration of cyclophosphamide and cisplatin until 2005 and a combination of carboplatin and taxol after 2005 [29].

    A total of 7,005 AEOC patients treated with NACT followed by IDS were analyzed, with 4,766 being in FIGO stage III and 2,285 in stage IV (Table S1). When considering only the studies comparing patients receiving ≤3 NACT cycles and ≥4 NACT cycles, no significant difference in the distribution of stages III and IV was detected (p=0.36) (Table S2). However, when considering only the studies comparing patients receiving ≤4 NACT cycles and ≥5 NACT cycles, an increased proportion of stage IV patients was observed in the patients receiving ≥5 NACT cycles (37.4% vs. 30.1%, respectively) (Table S3). Serous EOC was the main diagnosis in 5,725 (84.12%) patients, while the remaining 1,081 (15.88%) were diagnosed with other histotypes such as clear cell, endometrioid, mucinous and undifferentiated (Table S1).

    Only 3 studies [13, 19, 30] reported the response to NACT using the Response Evaluation Criteria in Solid Tumors criteria [34] and no significant differences were found between the early and delayed IDS groups. In terms of surgical details, there are only a few studies that have reported important information such as peritoneal cancer index, complications from surgical procedures, and complexity score. However, all studies have reported the completeness of cytoreduction (R0) that was achieved in 57.5% of 4,228 patients.

    Regarding the relationship between the number of NACT cycles and surgical parameters, most studies included in the systematic review did not find significant differences. Only Bacry et al. [23] found a meaningful difference between early and delayed IDS, reporting a higher number of posterior pelvectomies in patients undergoing IDS after ≤3 cycles of NACT without a noticeable increase in complications. When it comes to the completeness of cytoreduction (R0), Marchetti et al. [26] and Stoeckle et al. [30] were the only authors to find that a higher number of NACT cycles led to an increased rate of R0. However, this significant trend was opposite when pooling all studies together. Namely, when confronting patients receiving ≤3 NACT cycles and ≥4 NACT cycles, a lower proportion of R0 was observed in the case of NACT ≥4 (56%) vs. NACT ≤3 (71%) (Table S4). Same result was seen also when pooling the studies confronting patients receiving ≤4 NACT cycles and ≥5 NACT cycles (76.9% R0 vs. 70.9% R0, respectively) (Table S5).

    As far as the BRCA status is concerned, only 4 studies comparing patients receiving ≤4 NACT cycles and ≥5 NACT cycles reported this parameter. When pooling these results, no significant difference was seen between the groups (p=0.11) (Table S6).

    Regarding survival outcomes, 16 studies [13, 16, 17, 18, 19, 21, 22, 23, 26, 27, 28, 29, 30, 32, 33, 35] showed no significant differences in PFS and OS when comparing patients undergoing delayed or early IDS. In 6 studies [14, 15, 20, 24, 25, 31], an unfavorable outcome was linked to an increase in the number of NACT cycles prior to IDS. Interestingly, Stoeckle et al. [30] discovered a trend towards improved survival in patients undergoing delayed IDS (≥5 cycles of NACT), although the results were not statistically significant.

    2. Quality assessment

    The risk of bias in the papers included is reported in Table 2. Of the 22 studies, 15 (68.2%) were rated as "fair” out of which 12 (80%) with a score of 10/14, 1 (6.7%) with a score of 9/14, 2 (13.3%) with a score of 8/14; the remaining 7 (31.8%) were rated as “good.” with a score of 11/14. The low scores in the evaluation were largely the result of problems with the study design, particularly the absence of a sample size estimate and the lack of reporting on patients who were lost to follow-up. This information was only assessed in 2 studies [15, 23].

    Table 2
    Quality assessment of the selected studies

    3. Meta-analysis

    The criteria used to distinguish “early,” and “delayed” IDS varied across studies. In some, patients who underwent 4 cycles of NACT were considered “early,” while in others they were considered “delayed.” To prevent the introduction of potential bias, we chose to analyze these studies separately, given the alternating categorization of the 4-cycle group as both “early” and “delayed.”

    Out of the 22 studies, 15 [13, 14, 16, 17, 18, 19, 20, 21, 24, 26, 28, 29, 30, 33, 35] established 4 cycles as the threshold for “early” IDS and compared surgery after <4 cycles to surgery >5 or more cycles of NACT. The other 7 studies [15, 22, 23, 25, 27, 31, 32] established 3 cycles as the threshold for “early” IDS and compared surgery after ≤3 NACT cycles with surgery after ≥4 NACT cycles. Four studies did not have PFS analysis data, while all had OS data.

    4. Survival analysis in the 7 studies comparing ≤3 vs. ≥4 NACT cycles

    PFS

    Out of all the 22 articles included in our study, 7 (31.8%) had the NACT threshold set at 3 comprising 1,410 patients. Almost all studies [15, 22, 23, 25, 27, 32] (6; 85.7%) reported PFS data while the work by Altman et al. [31] did not provide any such data. No statistically significant difference in PFS was observed between patients who received 3 or fewer cycles and those who received 4 or more cycles prior to IDS (random effects model: HR=1.13; 95% CI=0.99–1.29; p=0.07) (Fig. 2A). The between-study heterogeneity variance was estimated at a Tau2<0.001; 95% CI=0–0.35 and I2=21.8%; 95% CI=0–66.2, suggesting that inconsistency between studies was minimal. The prediction interval ranged from g=0.94 to 1.36.

    Fig. 2
    The forest plot for PFS (A) and OS (B) in studies with a NACT threshold of 3 shows a trend towards a poorer prognosis for patients undergoing delayed IDS, but this did not reach statistical significance. HRs are for NACT ≥4/NACT ≤3 and 95% CI.
    CI, confidence interval; HR, hazard ratio IDS, interval debulking surgery; NACT, neoadjuvant chemotherapy; OS, overall survival; PFS, progression-free survival; SE, standard error.

    OS

    All 7 studies dividing patients into early and delayed IDS with a threshold of 3 NACT cycles reported OS data. The meta-analysis showed a statistically significant difference in survival between the 2 groups of patients, in favor of the patients receiving fewer NACT cycles (random effects model: HR=1.31; 95% CI=1.08–1.59; p=0.006) (Fig. 2B). The heterogeneity measured for this result was also low with a Tau2=0.01; 95% CI=0–0.26 and I2=16.1%; 95% CI=0–60.0, suggesting a minimal inconsistency between the included studies. The prediction interval ranged from g=0.89 to 1.92.

    5. Survival analysis in 15 studies comparing ≤4 vs. ≥5 NACT cycles

    PFS

    Fifteen studies (68.2%) comprising 5,595 patients had the NACT threshold set at 4 cycles. Out of these 15 studies, 11 (73.3%) [13, 14, 17, 19, 20, 21, 24, 26, 28, 33, 35] provided data on PFS. When pooling their results, a statistically significant difference in PFS was observed between patients who underwent ≤4 and ≥5 NACT cycles, with favorable outcomes in patients who received early IDS (random effects model: HR=1.22; 95% CI=1.08–1.36; p<0.001) (Fig. 3A). This corresponds to a 54.9% likelihood that the patients who receive more NACT cycles will experience recurrence first. The heterogeneity for this comparison was significant (p=0.03) Tau2=0.02; 95% CI=0–0.12 and I2=48.1%; 95% CI=0–73.4, suggesting moderate heterogeneity between studies. The prediction interval ranged from g=0.88 to 1.68. Outlier identification analysis revealed that the study by Liu et al. [20] could potentially be classified as an outlier as determined by the lack of overlap between the CI of their findings and the CI of the pooled effect. The reanalysis of the data excluding this study obtained similar results (random effects model: HR=1.17; 95% CI=1.06–1.31; p=0.002) with a reduction in heterogeneity (Tau2=0.01; 95% CI=0–0.07 and I2=32.2%; 95% CI=0–66.7, p=0.14). This indicates that the overall pooled effect was not heavily biased by outliers.

    Fig. 3
    Forest plot for PFS (A) and OS (B) of studies with a NACT threshold set at 4 shows a significant decline in PFS for patients who underwent delayed IDS. However, only a tendency towards a worse OS was noted. HRs are for NACT ≥5/NACT ≤4 and 95% CI.
    CI, confidence interval; HR, hazard ratio IDS, interval debulking surgery; NACT, neoadjuvant chemotherapy; OS, overall survival; PFS, progression-free survival; SE, standard error.

    OS

    All 15 studies (100%) with the NACT threshold set at 4 reported data on OS. The pooled analysis showed a 54.3% increased risk of death in patients who underwent ≥5 NACT cycles (random effects model: HR=1.19; 95% CI=1.07–1.32; p=0.002) (Fig. 3B). The heterogeneity for this comparison was bellow the significance level (p=0.12) estimated at a Tau2=0.01; 95% CI=0–0.13]; I2=30.5%; 95% CI=0%–62.6%. The prediction interval ranged from g=0.93 to 1.52. The same potential outlier study was identified and removed, and similar results were obtained (random effects model: HR=1.16; 95% CI=1.05–1.28; p=0.004), with an associated reduction in heterogeneity values (Tau2=0.006; 95% CI=0–0.05 and I2=4.4%; 95% CI=0–57], p=0.4).

    Given that paclitaxel was added to the standard chemotherapy regimen of OC patients after the GOG111 and OV10 trials, we excluded the studies enrolling patients before 1996 or not reporting paclitaxel as part of the patients treatments and report similar results (PFS: HR=1.2; 95% CI=1.06–1.35; p=0.003; and OS: HR=1.19; 95% CI=1.06–1.33; p=0.003) (Fig. S2).

    DISCUSSION

    To the best of our knowledge, the current systematic review and meta-analysis is the largest available analysis of women undergoing IDS after various cycles of NACT for AEOC. Our analysis revealed a lack of consensus about the optimal number of NACT cycles for the best survival outcomes. Most of the studies were retrospective with only one observational prospective study, and no prospective RCTs have been published to date. The studies analyzed were highly heterogeneous with respect to tumor characteristics, such as tumor histology (Table S1), number of NACT cycles before IDS and the reported surgical parameters (Table 1).

    Based on the years of publication data, it can be said that the debate on IDS timing has expanded in recent years, as approximately 45.5% of the studies were published in the last 3 years. Although there was an agreement regarding platinum based NACT, a standardized approach to determining the optimal number of NACT cycles prior to IDS has yet to be established.

    International guidelines recommend surgery at the earliest opportunity, ideally after 3 cycles. However, our analysis found that early IDS was usually performed after 4 cycles instead of 3 cycles in nearly twice as many studies (15 compared to 7). This result may be due to the multitude of factors that need to be considered when determining a patient's suitability for surgery, considering general health, response to chemotherapy, histotypes with different intrinsic response to therapy, surgical expertise and, availability of facilities [36].

    Data about surgery was lacking in some studies and it was highly variable. The works of Thomas et al. [24] and Marchetti et al. [26] had established that the number of cycles of NACT does not simplify the procedure or reduce the associated complications. This contradicts the notion that an increased number of NACT cycles would result in less aggressive surgery, as seen in gastrointestinal and breast cancer [37, 38].

    The completeness of cytoreduction is widely recognized as one of the most important prognostic factors for ovarian cancer but studies about IDS lack to stress this issue. Only the study by Yao et al. [21] reported that the number of NACT cycles did not affect survival, but complete cytoreduction was associated with a survival benefit [21]. Therefore, it is hypothesized that complete cytoreduction at the time of IDS, rather than the number of NACT cycles, may be associated with longer survival.

    In terms of the impact of NACT cycles number on survival outcomes, only a few studies showed a significant result [14, 15, 20, 24, 25, 31], while the remaining ones reported only a trend towards a worse outcome in patients receiving more NACT cycles. When all studies were pooled in the meta-analysis, a trend toward a decline in PFS and a significant decrease of OS with increasing number of NACT cycles was observed. In any case, when analyzing studies comparing only ≤3 vs. ≥4 cycles of NACT, the number of patients included in the studies was small, which could explain the borderline statistical significance in case of PFS. Conversely, a significant difference in terms of PFS was found in patients who received ≤4 cycles compared to those who received ≥5 NACT cycles, with a negative impact in the case of delayed IDS. This significance was also maintained in the OS analysis.

    Our meta-analysis showed a worse prognosis in patients undergoing IDS after a higher number of NACT cycles. However, the decision-making process behind extending the number of NACT cycles is seldom clearly specified. The reasons for this decision can vary based on factors such as advanced age, the overall health condition of the patient which may hinder their ability to undergo major surgery and necessitate additional treatment cycles, as well as a diminished response to chemotherapy leading to the selection of patients with platinum-resistant clones [39]. Therefore, multiple contributing factors can lead to a worse prognosis independent of the number of chemotherapy cycles [23, 24]. Given that the decision to increase the number of cycles depends on the clinical evaluation of the patient and the individual tumoral response (usually an interim evaluation after 3–4 cycles by CA-125 and CT scan), the strength of these significant results is limited to concluding that a higher number of cycles is associated with a detrimental outcome, but the putative causative effect can be demonstrated solely in the setting of a RCT. The 2 ongoing RCTs: the CHRONO trial (NCT03579394) and the GOGER trial (NCT02125513) should provide more consistent proof in this regard.

    Our systematic review and meta-analysis have several strengths. Firstly, it included a large number of reports, pooling together data from 7,005 AEOC patients. This represents a significant cohort, given the rarity of the disease and the advanced stage of the tumor. Secondly, separate analyses were conducted to account for differences in the threshold for NACT cycles (3 or 4 cycles), as heterogeneity was observed in this aspect due to inconsistent inclusion of patients receiving 4 cycles in early and delayed IDS.

    However, our work has some limitations. Firstly, the heterogeneity of the studies limited the evaluation to only PFS and OS as clinical outcomes, excluding other potentially important variables. Secondly, patient enrollment took place over a long period of time (in some cases over 10 years), during which diagnosis and treatment schemes may have slightly varied. Although almost all patients in the meta-analysis received platinum-based chemotherapy, one study included a combination of other drugs such as ifosfamide, epirubicin, and cisplatin in patients treated before 2005 [29]. However, this potential bias is expected to have a minimum impact due to the relatively small number of patients from this single study compared to the entire population included in this meta-analysis.

    In conclusion, our investigation highlights the need to further evaluate the ideal number of NACT cycles, as this aspect has yet to be determined based on the currently available body of research. Despite evidence suggesting a possible relationship between NACT cycles and progression, the correlation with survival outcomes requires cautious interpretation considering the presence of various confounding factors. To establish a clear understanding, it is imperative to undertake additional rigorous research in the form of RCTs as chemotherapy schemes can impact both the overall success of the treatment and the patient's quality of life. A clear understanding of the optimal number of cycles is crucial for clinicians to ensure the best possible outcomes for their patients.

    SUPPLEMENTARY MATERIALS

    Table S1

    Overall distribution of OC histotypes and stages of the patients from the studies included in the meta-analysis

    Click here to view.(27K, xls)

    Table S2

    Analysis of the distribution of International Federation of Gynecology and Obstetrics ovarian cancer stages between patients receiving ≤3 NACT cycles and ≥4 NACT cycles

    Click here to view.(27K, xls)

    Table S3

    Analysis of the distribution of International Federation of Gynecology and Obstetrics ovarian cancer stages between patients receiving ≤4 NACT cycles and ≥5 NACT cycles

    Click here to view.(28K, xls)

    Table S4

    Analysis of the distribution of residual disease after surgery between patients receiving ≤3 NACT cycles and ≥4 NACT cycles

    Click here to view.(27K, xls)

    Table S5

    Analysis of the distribution of residual disease after surgery between patients receiving ≤4 NACT cycles and ≥5 NACT cycles

    Click here to view.(27K, xls)

    Table S6

    Analysis of the distribution of BRCA genotypes between patients receiving ≤4 NACT cycles and ≥5 NACT cycles

    Click here to view.(27K, xls)

    Fig. S1

    Distribution of the published studies included in our systematic review and meta-analysis by year. Funnel plots evaluating the publication bias of the studies. Egger’s test for funnel plot asymmetry is reported above each graph.

    Click here to view.(643K, ppt)

    Fig. S2

    Forest plot for PFS (A) and OS (B) of studies with a NACT threshold set at 4 (excluding those without paclitaxel) shows a significant decline in PFS for patients who underwent delayed IDS. However, only a tendency towards a worse OS was noted. HRs are for NACT ≥5/NACT ≤4 and 95% CI.

    Click here to view.(1M, ppt)

    Notes

    Funding:This research was partially funded ALMA IDEA22 line A D.M. 737/2021 from the European Union “NextGenerationEU” CUP J45F21002000001.

    Conflict of Interest:No potential conflict of interest relevant to this article was reported.

    Author Contributions:

    • Conceptualization: D.P., P.A.M.

    • Data curation: C.C.A., D.G., R.G.

    • Formal analysis: C.C.A., D.G., R.G.

    • Investigation: D.G., R.G.

    • Methodology: C.C.A., D.G., R.G.

    • Project administration: Z.C., D.P.

    • Resources: P.A.M.

    • Supervision: P.A.M.

    • Validation: T.M., F.E., D.M., G.S., B.A., H.P., A.S.

    • Visualization: T.M., F.E., D.M., G.S., B.A., H.P., A.S.

    • Writing - original draft: C.C.A., D.G., R.G.

    • Writing - review & editing: D.S., D.P., P.A.M.

    ACKNOWLEDGEMENTS

    This work was done under the financing of ALMA IDEA22 line A D.M. 737/2021 from the European Union “NextGenerationEU,” CUP J45F21002000001. We would like to extend our gratitude to Claudia Cavicchi from the University Library System of Bologna for her contribution in constructing the research strings and executing database queries.

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    MeSH Terms
    Carcinoma, Ovarian Epithelial*
    Cytoreduction Surgical Procedures
    Drug Therapy
    Humans
    Neoadjuvant Therapy*
    Ovarian Neoplasms
    Prognosis
    Progression-Free Survival*
    Systematic Review*
    Metrics
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