# Identifying high-risk relapse in early-stage I to II ovarian cancer using the CA125 ELIMination rate constant K (KELIM) score: a Gynecologic Cancer InterGroup individual patient-data meta-analysis

Pauline Corbaux, Benoit You, Tatsuo Kagimura, Rosalind Glasspool, Iain Mcneish, Adrian Cook, Mansoor Mirza, Kristina Lindemann, Anna Tinker, Stephen Welch, et al.

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Pauline Corbaux, Benoit You, Tatsuo Kagimura, Rosalind Glasspool, Iain Mcneish, et al. Identifying high-risk relapse in early-stage I to II ovarian cancer using the CA125 ELIMination rate constant K (KELIM) score: a Gynecologic Cancer InterGroup individual patient-data meta-analysis. International Journal of Gynecological Cancer, 2026, 36 (1), pp.102719. 10.1016/j.ijgc.2025.102719. hal-05395685

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# Identifying high-risk relapse in early-stage I to II ovarian cancer using the CA125 ELIMination rate constant K (KELIM) score: a Gynecologic Cancer InterGroup individual patient-data meta-analysis

<figure><img src="image_2.png" /></figure>

Pauline Corbaux<sup>a,b</sup>, Benoit You<sup>a,c,*</sup>, Tatsuo Kagimura<sup>d</sup>, Rosalind M. Glasspool<sup>e</sup>, Iain McNeish<sup>f</sup>, Adrian Cook<sup>g</sup>, Mansoor R. Mirza<sup>h,i</sup>, Kristina Lindemann<sup>j</sup>, Anna V. Tinker<sup>k</sup>, Stephen Welch<sup>l</sup>, Isabelle L. Ray-Coquard<sup>m</sup>, Fabien Subtil<sup>n</sup>, Olivier Colomban<sup>a</sup>, Julien Péron<sup>c,n</sup>, Eleni Karamouza<sup>o,p</sup>, Caroline Kelly<sup>q</sup>, Liz-Anne Lewsley<sup>q</sup>, Xavier Paoletti<sup>r</sup>, Nozomu Yanaihara<sup>s</sup>

Received 25 July 2025, Accepted 4 October 2025; Available online 10 October 2025

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## ABSTRACT

**Objective:** Despite curative surgery and adjuvant chemotherapy, a significant number of early stage I to II ovarian cancers relapse. The CA125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor intrinsic chemosensitivity in advanced epithelial ovarian cancer. We assessed the prognostic value of KELIM in patients with early-stage ovarian cancer, with respect to 5-year recurrence-free survival and overall survival, using the Meta-Analysis in Ovarian Cancer, which is the Gynecologic Cancer InterGroup individual patient-data meta-analysis of randomized trials evaluating different adjuvant chemotherapy regimens.

**Methods:** Individual patient KELIM values were previously estimated in 5884 patients from the Meta-Analysis in Ovarian Cancer. The prognostic value of KELIM was assessed using univariable & multivariable analyses in patients with resected International Federation of Gynecology and Obstetrics stage I and II disease.

**Results:** Overall, 1143 patients were identified, including clear cell (46.7%); serous (23.7%); endometrioid (12.4%); and mucinous carcinomas (3.9%). In multivariable analyses, a favorable KELIM score (≥1.0) was associated with higher 5-year recurrence-free survival (68.3% vs 55.9%; HR 0.61, 95% CI 0.48 to 0.77) and 5-year overall survival (80.7% vs 72.8%; HR 0.50, 95% CI 0.36 to 0.68), as was the histological sub-type. In exploratory analyses, KELIM score was a prognostic factor regarding 5-year recurrence-free survival and overall survival across all sub-types (especially clear cell carcinoma and serous, with HR ranging from 0.45 to 0.63) with baseline CA125 ≥15 IU/L, except for mucinous histology.

**Conclusions:** The pragmatic KELIM score is an independent prognostic factor in patients with a non-mucinous stage I to II ovarian cancer optimally resected and treated with adjuvant chemotherapy. KELIM may help identify the patients at higher risk of relapse and death requiring closer follow-up or treatment intensification.

## WHAT IS ALREADY KNOWN ON THIS TOPIC

Despite optimal surgical resection and adjuvant platinum-based chemotherapy, a substantial proportion of patients with early-stage (International Federation of Gynecology and Obstetrics stage I-II) epithelial ovarian cancer experience disease recurrence and cancer-related mortality. In advanced ovarian cancer, the CA125 ELIMination rate constant K (KELIM) score (based on the longitudinal CA125 kinetics observed during first-line chemotherapy) has shown independent prognostic value for survival beyond surgical outcomes. However, its prognostic relevance in early-stage disease had yet to be established.

## WHAT THIS STUDY ADDS

This individual patient-data meta-analysis of randomized trials demonstrates that KELIM is an independent prognostic factor for both 5-year recurrence-free survival and overall survival in patients with non-mucinous early-stage epithelial ovarian cancer treated with adjuvant chemotherapy following primary surgery, provided the baseline CA125 levels was > 15 IU/L.

## HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY

The CA125 elimination kinetics KELIM (that is easily calculable online) could help clinicians identify patients at higher risk of recurrence and mortality despite optimal surgical and medical treatment. These high-risk patients could benefit from more tailored management strategies, such as closer surveillance or intensified adjuvant therapy.

<footnote>* Correspondence to Dr Benoit You, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL). Early phase trial unit in oncology (CITOHL-EPSILYNON), Centre Hospitalier Lyon-Sud, Service d'oncologie médicale, Chemin du Grand Revoyet, 69495 Pierre-Benite, France; benoit.you@chu-lyon.fr (B. You)</footnote>
Keywords:

CA125 KELIM; Mathematical Modeling; Prognostic Biomarker; Epithelial Ovarian Cancer; Early-Stage Ovarian Cancer

INTRODUCTION

Overall, 10% to 20% of women with epithelial ovarian cancer are diagnosed at an early stage (International Federation of Gynecology and Obstetrics [FIGO] stage I or II)¹ and are eligible for curative care. The standard treatment involves a carcinologic staging surgery, usually followed by adjuvant platinum-based chemotherapy,²,³ and is associated with excellent long-term outcomes. The 5-year overall survival ranges from 70% for FIGO stage IC-II to 90% for stage IA-IB. The 5-year recurrence-free survival is 65% to 80%.⁴,⁵

Early-stage epithelial ovarian cancer is a heterogeneous entity. While high-
grade serous carcinoma remains the most frequent sub-type, other histologies
(such as clear cell, endometrioid, and mucinous carcinomas) are proportionally
more common than in advanced-stage disease, and are associated with
distinct prognoses.⁶

A significant number of patients with early-stage epithelial ovarian cancer experience relapse, and may eventually die from their ovarian cancer. The benefit of adjuvant platinum-based chemotherapy for improving recurrence-free and overall survival has been demonstrated in large phase III trials (ICON-1 and ACTION) and confirmed in a Cochrane systematic meta-analysis.²,⁷,⁸ This benefit appears particularly pronounced in patients with unfavorable prognostic features, such as stage IA grade 3, stage IB or IC grade 2 to 3, or clear cell histology.⁹ However, the extent to which women without these unfavorable features derive a similar benefit remains uncertain. Consequently, current clinical guidelines recommend that adjuvant chemotherapy decisions be guided by risk stratification based on established prognostic factors.³

Recently, the modeled CA125 ELIMination rate constant K (KELIM), based on the CA125 longitudinal kinetics within the first 100 treatment days of the first-line chemotherapy, was developed to reflect the early serum tumor marker elimination rate during systemic treatment during neo-adjuvant or adjuvant chemotherapy in patients with newly diagnosed stage III-IV ovarian cancer.¹⁰,¹¹ It was shown to be a reproducible pragmatic indicator of tumor chemosensitivity, in neo-adjuvant setting, and a strong prognostic factor in those treated with adjuvant chemotherapy after primary debulking surgery. The prognostic value regarding survival was reproducibly shown to be complementary to the surgery outcome based on the residual post-operative lesions.¹⁰⁻¹² A higher CA125 KELIM value indicates a faster CA125 elimination and better prognosis. To facilitate clinical interpretation, KELIM is standardized by the median value, then dichotomized into a KELIM score: standardized KELIM <1.0 is considered unfavorable, while standardized KELIM ≥1.0 is favorable. KELIM score helps interpret the chemotherapy efficacy in routine practice, as suggested by the growing number of calculations on the online calculator biomarker.kinetics (https://www.biomarker-kinetics.org/) worldwide (with about 30,000 patients/year).

The prognostic role of KELIM in early-stage epithelial ovarian cancer has
not been evaluated so far.

The objective of this study was to analyze the Meta-Analysis in OVarian
cancer (MAOV) individual patient-data meta-analysis dataset for evaluating the
prognostic value of the KELIM score in patients with surgically managed stage
I to II epithelial ovarian cancer, across histological sub-types, to better identify
the patients more likely to relapse and die from their disease despite an
adequate surgical and medical treatment.

METHODS

Trial Selection and Estimation of Individual KELIM

The present study is an ancillary analysis of the MAOV meta-analysis of indi-
vidual patient data,¹²,¹³ for which the study selection has been reported else-
where.¹³ In summary, MAOV included randomized clinical trials evaluating first-
line systemic treatments in patients with previously untreated ovarian carcinoma
regardless of FIGO stages, published between 2001 and 2016. Patients were
eligible for KELIM estimation if at least 3 serum CA125 measurements during
the first 100 days of first-line treatment (excluding maintenance) were available.
Based on these criteria, individual KELIM values were previously determined for
5884 patients from 8 selected trials¹² (CCTG-OV.16,¹⁴ JGOG-3016,¹⁵ JGOG-

3017,¹⁶ GINECO-2007,¹⁷ MRC-ICON7,¹⁸ NSGO-2012,¹⁹ SCOTROC-1,²⁰ SCOTROC-4²¹). Briefly, individual CA125 longitudinal kinetics were characterized using a population-based approach, with the non-linear mixed effect model previously reported (Supplementary Text).²²,²³ In this additional analysis, we focused on patients with FIGO stage I-II disease who underwent optimal surgery, defined in the database as having post-operative residual disease <1 cm.

KELIM Prognostic Value

To assess the prognostic value of KELIM for overall and recurrence-free survival, survival was analyzed using Kaplan-Meier curves with log-rank tests. HRs were estimated with univariable and multivariable Cox models to account for other prognostic factors, such as FIGO stage and histological sub-types, and treatment arms. Analyses were implemented with a landmark time point set-up at 100 days after randomization, excluding patients who died or progressed within this period, to avoid potential biases related to early events and CA125 kinetics.²⁴

Exploratory sub-group analyses were conducted according to different levels of baseline CA125 at the beginning of adjuvant chemotherapy (<15 IU/mL; ≥15 IU/mL; ≥25 IU/L; and ≥35 IU/mL), and to different histological sub-types (serous; clear cell carcinoma; endometrioid carcinoma; and mucinous carcinoma). Analyses were stratified on trials with adjustments for multiple studies.

Statistical Analyses and Computing Process

NONMEM 7.5 software (ICON development Solutions, USA) was used to fit CA125 kinetics to the semi-mechanistic model.²⁵ Parameters were estimated using maximum likelihood and the stochastic approximation of expectation maximization algorithm.²⁶ Survival and logistic analyses were performed in R software version 4.2.2. The adjusted Wilcoxon *p*-values were obtained using the Dunn test with Bonferroni adjustment to account for multiple comparisons. Statistical tests were performed with a two-sided alpha risk of 0.05.

Ethics Approval and Consent to Participate

The Ethics Committee of Gustave Roussy Cancer Center, Villejuif, France, approved this study, and the French data protection authority waived the need for informed consent for the use of deidentified data.

In accordance with the journal's guidelines, we will provide our data for
independent analysis by a team selected by the Editorial Team for the pur-
poses of additional data analysis or for the reproducibility of this study in other
centers if such is requested.

RESULTS

Of the 5884 patients from the 8 trials previously analyzed in the MAOV
database, 1328 patients (22.6%) enrolled in 7 randomized clinical trials had
FIGO stage I/II disease (Fig. S, Table 1, Table S1). Except for the GINECO-2007
trial that focused on FIGO stage III or IV, all studies enrolled patients with FIGO
stage II disease, while 4 trials also included patients with FIGO stage I ovarian
cancers (JGOG-3017, MRC-ICON7, SCOTROC-1 and SCOTROC-4 trials). All
these trials investigated alternative platinum-based chemotherapy regimens in
comparison with the standard of care, carboplatin–paclitaxel, except for the
SCOTROC-4 trial, which investigated an intra-patient dose escalation from
single-agent carboplatin to a flat dose (Table 1, Table S1). Data about post-
operative residual disease was available for 99.2% of the patients. In total,
1143 patients (86.1%) from 7 randomized clinical trials operated with an
optimal surgical resection were included in the present study: 628 patients
with FIGO stage I (54.9%), and 515 patients with FIGO stage II disease (45.1%)
(Fig. S).

Clear cell carcinoma was the most frequent histological sub-type (n = 534 patients, 46.7%), followed by serous carcinoma (n = 271, 23.7%), endometrioid carcinoma (n = 142, 12.4%), and mucinous carcinoma (n = 44; 3.8%). Moreover, 127 patients (11.1%) had other epithelial sub-types, while the histological sub-type was unknown for 25 patients (2.2%). Of note,
<table><caption>**Table 1** Baseline Characteristics and KELIM According to Histological Sub-types.</caption><thead><tr><th>Characteristics</th><th>Clear cell carcinoma</th><th>Serous carcinoma</th><th>Endometrioid carcinoma</th><th>Mucinous carcinoma</th><th>Other type of epithelial carcinoma</th><th>Unknown histological type</th><th>Total</th></tr></thead><tbody><tr><td>Number of patient (%)</td><td>534 (46.7)</td><td>271 (23.7)</td><td>142 (12.4)</td><td>44 (3.8)</td><td>127 (11.1)</td><td>25 (2.2)</td><td>1143 (100)</td></tr><tr><td>FIGO stage, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>FIGO I</td><td>416 (66.2)</td><td>66 (10.5)</td><td>54 (8.6)</td><td>26 (4.1)</td><td>56 (8.9)</td><td>10 (1.6)</td><td>628 (55.0)</td></tr><tr><td>FIGO II</td><td>118 (22.9)</td><td>205 (39.8)</td><td>88 (17.1)</td><td>18 (3.5)</td><td>71 (13.8)</td><td>15 (2.9)</td><td>515 (45.0)</td></tr><tr><td>Chemotherapy regimen, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Carboplatin + paclitaxel based</td><td>313 (44.3)</td><td>204 (28.9)</td><td>88 (12.5)</td><td>22 (3.1)</td><td>54 (7.6)</td><td>25 (3.5)</td><td>706 (61.8)</td></tr><tr><td>Carboplatin + docetaxel</td><td>9 (11.3)</td><td>24 (30.0)</td><td>13 (16.3)</td><td>10 (12.5)</td><td>24 (30.0)</td><td>0 (0)</td><td>80 (7.0)</td></tr><tr><td>Carboplatin monotherapy</td><td>14 (8.8)</td><td>43 (27.0)</td><td>41 (25.8)</td><td>12 (7.5)</td><td>49 (30.8)</td><td>0 (0)</td><td>159 (13.9)</td></tr><tr><td>Cisplatin based</td><td>198 (100)</td><td>0 (0)</td><td>0 (0)</td><td>0 (0)</td><td>0 (0)</td><td>0 (0)</td><td>198 (17.3)</td></tr><tr><td>Initial CA125 (IU/mL)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Median (Q1-Q3)</td><td>42.0 (21.7-91.8)</td><td>37.0 (19.5-100.9)</td><td>36.0 (15.0-73.8)</td><td>23.5 (14.0-70.8)</td><td>26.0 (13.0-72.5)</td><td>20.0 (13.0-71.2)</td><td>37.1 (18.2-89.5)</td></tr><tr><td>≥35 IU/mL, n (%)</td><td>305 (57.1)</td><td>140 (51.7)</td><td>73 (51.4)</td><td>18 (40.9)</td><td>52 (40.9)</td><td>11 (44.0)</td><td>599 (52.4)</td></tr><tr><td>≥25 IU/mL, n (%)</td><td>379 (71.0)</td><td>186 (68.6)</td><td>85 (59.9)</td><td>21 (47.7)</td><td>67 (52.8)</td><td>11 (44.0)</td><td>749 (65.5)</td></tr><tr><td>≥15 IU/mL, n (%)</td><td>462 (86.5)</td><td>219 (80.8)</td><td>110 (77.5)</td><td>31 (70.5)</td><td>92 (72.4)</td><td>18 (72.0)</td><td>932 (81.5)</td></tr><tr><td>&lt; 15 IU/mL, n (%)</td><td>72 (34.1)</td><td>52 (24.6)</td><td>32 (15.2)</td><td>13 (6.2)</td><td>35 (16.6)</td><td>7 (3.3)</td><td>211 (18.5)</td></tr><tr><td>KELIM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Continuous value (d<sup>-1</sup>), median (Q1-Q3)</td><td>0.079 (0.063-0.096)</td><td>0.071 (0.057-0.086)</td><td>0.069 (0.055-0.077)</td><td>0.065 (0.057-0.082)</td><td>0.066 (0.054-0.080)</td><td>0.070 (0.058-0.082)</td><td>0.074 (0.058-0.090)</td></tr><tr><td>Standardized continuous value, median (Q1-Q3)</td><td>1.32 (1.05-1.61)</td><td>1.18 (0.96-1.43)</td><td>1.16 (0.91-1.47)</td><td>1.08 (0.95-1.37)</td><td>1.11 (0.90-1.34)</td><td>1.16 (0.97-1.37)</td><td>1.23 (0.97-1.51)</td></tr><tr><td>Favorable KELIM score (≥1), n (%)</td><td>425 (79.6)</td><td>192 (70.8)</td><td>93 (65.5)</td><td>25 (56.8)</td><td>81 (63.8)</td><td>17 (68.0)</td><td>833 (72.9)</td></tr></tbody></table>

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; Q1, first quartile; Q3, third quartile; KELIM, ELIMination rate constant K.

the JGOG-3017 study included patients with clear cell carcinomas only, who accounted for 34.7% of the present study population (n = 397), including 338 patients (85.1%) with FIGO stage I disease.

The baseline characteristics and KELIM according to histological sub-types are detailed in Table 1. The median post-operative CA125 level was 37.1 IU/mL (interquartile range [IQR] 18.2-89.5). Overall, 52.4% of patients (n = 599) had values above the conventional upper normal limit (≥35 IU/mL), and 81.5% of patients (n = 932) had baseline CA125 levels ≥15 IU/mL. Initial CA125 levels were higher in patients with clear cell carcinoma than in the other sub-types (median 42.0 vs 26.0 IU/mL, Wilcoxon adjusted *p* = .009) and in patients with FIGO stage II versus I (median 39.0 vs 36.0 IU/mL, Wilcoxon *p* < .0001).

The median of individual brut KELIM values was 0.074 d⁻¹ (IQR 0.058-0.090), ranging from 0.065 d⁻¹ to 0.079 d⁻¹ across histological sub-types (Table 1). Patients with clear cell carcinoma had significantly higher values (median 0.079 d⁻¹) compared with serous (0.071 d⁻¹; Wilcoxon adjusted *p* < .0001), endometrioid (0.069 d⁻¹, *p* = .008), mucinous (0.065 d⁻¹, *p* = .033), and other histologies (0.066 d⁻¹, *p* < .0001). In total, 72.9% (833 patients) had a favorable KELIM score using the same cut-off as those used for the previous publication of MAOV (0.06 d⁻¹).

With a median follow-up of 46.9-month (95% CI 45.0 to 48.0) for overall survival, 188 patients (16.5%) had died, and 335 (29.7%) had experienced disease recurrence or died without documented recurrence. The corresponding 5-year overall survival and recurrence-free survival rates were 79.2% (95% CI 76.0 to 82.5) and 64.8% (95% CI 61.2 to 68.5), respectively.

The data from 1128 patients were assessable for recurrence-free survival analyses. The patients with a favorable KELIM score experienced higher 5-year

recurrence-free survival rates than those with an unfavorable KELIM score: 68.3% (95% CI 64.1 to 72.5) versus 55.9% (95% CI 49.3 to 62.5), log-rank *p*-value < .0001, HR 0.59; (95% CI 0.47 to 0.74), translating in an absolute difference of 12.4% of risk of relapse at 5 years. Median recurrence-free survival was not reached in patients presenting with a favorable KELIM score (non-reached [NR]-NR) versus NR months (95% CI 51.1-NR) in those with an unfavorable score. Recurrence-free survival curves according to KELIM score are shown in Figure 1A.

In multivariable Cox analyses, a favorable KELIM score was independently associated with a better recurrence-free survival (favorable KELIM vs unfavorable, HR 0.61; 95% CI 0.48 to 0.77, *p* = .0001), as were the FIGO stage (FIGO stage II vs I, HR 1.65; 95% CI 1.24 to 2.19, *p* = .0005), and an endometrioid histological sub-type (endometrioid carcinoma vs serous carcinoma, HR 0.42; 95% CI 0.28 to 0.64, *p* < .0001) (Table 2).

Exploratory sub-group analyses were performed to assess KELIM prognostic value according to different initial CA125 value cutoffs at the beginning of adjuvant chemotherapy. While KELIM exhibited no prognostic value in patients with initial CA125 <15 IU/mL, a consistent independent prognostic value was observed as soon as the initial CA125 level was ≥15 IU/mL (Table S2). The recurrence-free survival curves in patients with initial CA125 level ≥15 IU/mL across histological sub-types are shown in Figure 2. In multivariable analyses, KELIM score was a significant and independent prognostic factor regarding recurrence-free survival in patients with a serous carcinoma (HR 0.55, 95% CI 0.36 to 0.85, *p* = .005) and in those with a clear cell carcinoma (HR 0.63, 95% CI 0.42 to 0.97, *p* = .034). In patients with an endometrioid carcinoma, KELIM was not a statistically significant prognostic factor although the HR suggested a potential favorable effect (HR 0.78, 95% CI
<figure><img src="image_3.png" /><figcaption>**Figure 1** Kaplan-Meier curves according to KELIM score for RFS (A) and OS (B). KELIM, ELIMination rate constant K.</figcaption></figure>

<table><caption>**Table 2** Univariable and Multivariable Recurrence-Free Survival and Overall Survival Analyses.</caption><thead><tr><th rowspan="3">Covariates</th><th rowspan="3">Classes</th><th colspan="4">Recurrence-free survival</th><th colspan="4">Overall survival</th></tr><tr><th colspan="2">Univariable</th><th colspan="2">Multivariable</th><th colspan="2">Univariable</th><th colspan="2">Multivariable</th></tr><tr><th>5-year survival (%), 95% CI</th><th>p-Value</th><th>HR (95% CI)</th><th>p-Value</th><th>5-year survival (%)</th><th>p-Value</th><th>HR (95% CI)</th><th>p-Value</th></tr></thead><tbody><tr><td rowspan="2">KELIM score</td><td>Unfavorable (&lt; 1.0)</td><td>55.9 (49.3 to 62.5)</td><td rowspan="2">&lt;.0001</td><td rowspan="2">REF</td><td rowspan="2">0.0001</td><td rowspan="2">72.8 (66.3 to 79.3)</td><td rowspan="2">&lt;.0001</td><td rowspan="2">REF</td><td rowspan="2">&lt;.0001</td></tr><tr><td>Favorable (≥1.0)</td><td>68.3 (64.1 to 72.5)</td><td>80.7 (77.0 to 84.4)</td><td>0.50 (0.36 to 0.68)</td></tr><tr><td rowspan="2">FIGO stage</td><td>I</td><td>75.1 (71.0 to 79.4)</td><td rowspan="2">&lt;.0001</td><td rowspan="2">REF</td><td rowspan="2">0.0003</td><td rowspan="2">81.7 (77.6 to 86.0)</td><td rowspan="2">.34</td><td rowspan="2">-</td><td rowspan="2">-</td></tr><tr><td>II</td><td>55.2 (50.2 to 60.6)</td><td>76.2 (71.8 to 81.0)</td><td>-</td></tr><tr><td rowspan="5">Histological sub-type</td><td>Serous</td><td>49.3 (42.3 to 57.6)</td><td rowspan="5">&lt;.0001</td><td rowspan="5">REF</td><td rowspan="5">-</td><td rowspan="5">76.4 (69.9 to 83.5)</td><td rowspan="5">.006</td><td rowspan="5">REF</td><td rowspan="5">-</td></tr><tr><td>Clear cell</td><td>72.7 (68.4 to 77.3)</td><td>78.0 (73.7 to 82.5)</td><td>1.84 (1.17 to 2.90)</td><td>.008</td></tr><tr><td>Endometrioid</td><td>73.5 (64.8 to 83.3)</td><td>91.7 (86.5 to 97.1)</td><td>0.33 (0.17 to 0.66)</td><td>.002</td></tr><tr><td>Mucinous</td><td>55.2 (29.9 to 100)</td><td>67.1 (42.0 to 100)</td><td>0.93 (0.42 to 2.08)</td><td>.86</td></tr><tr><td>Other</td><td>56.3 (44.6 to 71.1)</td><td>65.7 (51.3 to 84.1)</td><td>1.12 (0.65 to 1.95)</td><td>.62</td></tr><tr><td rowspan="2">Treatment group</td><td>Control</td><td>64.9 (59.6 to 70.6)</td><td rowspan="2">.41</td><td rowspan="2">-</td><td rowspan="2">-</td><td rowspan="2">78.5 (73.9 to 83.4)</td><td rowspan="2">.42</td><td rowspan="2">-</td><td rowspan="2">-</td></tr><tr><td>Experimental</td><td>64.6 (60.0 to 69.7)</td><td>78.5 (74.3 to 83.0)</td><td>-</td></tr></tbody></table>

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; KELIM, ELIMination rate constant K; REF, reference.
<figure><img src="image_4.png" /><figcaption>**Figure 2** Kaplan-Meier RFS curves according to KELIM score (favorable vs unfavorable) in patients with baseline CA125 ≥15 IU/mL treated for a serous carcinoma (A); a clear cell carcinoma (B); an endometrioid carcinoma (C); and a mucinous carcinoma (D). KELIM, ELIMination rate constant K; NR, not reported; RFS, recurrence-free survival.</figcaption></figure>

0.33 to 1.82, *p* = .56). However, the KELIM score was not a prognostic factor in patients with a mucinous carcinoma (HR 1.52, 95% CI 0.28 to 8.29, *p* = .63) (Table S3).

The data from 1140 patients (99.7%) were assessable for overall survival analysis. With a 46.9-month median follow-up (95% CI 45.0 to 48.0), patients with a favorable KELIM score (≥1.0) had a significantly higher overall survival compared to those with an unfavorable score (<1.0), with an absolute difference of 7.9% at 5 years. The 5-year overall survival rates were 80.7% (95% CI 77.0 to 84.4) and 72.8% (95% CI 66.3 to 79.3), respectively (log-rank *p* < .0001, HR 0.51, 95% CI 0.38 to 0.69). The median overall survival was not reached in patients with a favorable KELIM score (NR-NR)

compared to 71.1 months (67.8-NR) in those presenting with an unfavorable KELIM score (Fig. 1B).

The independent prognostic value of KELIM score regarding overall survival was confirmed with respect to the other covariates in multivariable analyses, with a HR of 0.50 (95% CI 0.36 to 0.68, *p* < .0001). FIGO stage was not associated with overall survival (Table 2). Patients with a clear cell histology had a worse prognosis (HR 1.84, 95% CI 1.17 to 2.90, *p* = .008), whereas those with an endometrioid histological sub-type tumors had a longer overall survival (HR 0.33, 95% CI 0.17 to 0.66, *p* = .002).

Like for recurrence-free survival analyses, KELIM score exhibited a consistent independent prognostic value when the initial CA125 level at the
beginning of the adjuvant chemotherapy was ≥15 IU/mL in multivariable analyses (Table S2). A favorable score was independently associated with a better overall survival in patients with a serous carcinoma (HR 0.50, 95% CI 0.26 to 0.96, *p* = .0439), and in those with a clear cell carcinoma (HR 0.45, 95% CI 0.29 to 0.72, *p* < .001) as soon as initial CA125 level was ≥15 IU/mL. Consistent with recurrence-free survival outcomes, the signal did not reach statistical significance in endometrioid carcinoma (HR 0.93, 95% CI 0.21 to 4.13, *p* = .92), and KELIM score did not exhibit any prognostic value in mucinous carcinoma (HR 1.41, 95% CI 0.17 to 11.55, *p* = .75) (Fig. 3, and Table S3).

DISCUSSION

Summary of Main Results

This study, based on a large individual patient-data meta-analysis database, highlights the potential role of the KELIM score as an independent prognostic biomarker for recurrence and overall survival in patients with optimally resected FIGO stages I and II non-mucinous ovarian carcinomas treated with adjuvant chemotherapy. The HRs of 0.59 for recurrence-free survival and 0.51 for overall survival, with absolute ~12 and ~8% differences between the 2 groups, indicate clinically significant relevant differences, comparable to those reported in patients with advanced FIGO stage III and IV diseases.²²,²³,²⁷⁻³⁰

<figure><img src="image_5.png" /><figcaption>**Figure 3** Kaplan-Meier OS curves according to KELIM score (favorable vs unfavorable) in patients with baseline CA125 ≥15 IU/mL treated for a serous carcinoma (A); a clear cell carcinoma (B); an endometrioid carcinoma (C); and a mucinous carcinoma (D). KELIM, ELIMination rate constant K; NR, not reached; OS, overall survival.</figcaption></figure>
The explorative sub-group analyses suggested that KELIM prognostic value was relevant as soon as the initial CA125 was ≥15 IU/mL at the beginning of the adjuvant chemotherapy. The prognostic value of KELIM was clinically highly relevant in patients with a serous sub-type, which is the most frequent ovarian cancer histology. More surprisingly, KELIM exhibited a clinically and statistically prognostic value in clear cell carcinoma, although this disease is known to be relatively resistant to conventional chemotherapy. Clear cell ovarian carcinoma is a distinct epithelial sub-type with unique clinical and biological features. Most cases are diagnosed at an early stage with more favorable outcomes, whereas advanced disease often exhibits intrinsic resistance to platinum-based chemotherapy.³¹ Post-operative CA125 level is already established as a prognostic marker, with normalization predicting better survival.³² Although a delayed effect of surgery on CA125 levels cannot be excluded, these findings suggest that KELIM may provide meaningful risk stratification in early-stage clear cell carcinoma.

In endometrioid carcinomas, the KELIM score was not significantly asso-
ciated with recurrence-free survival and overall survival. However, the HRs
suggested a numerically favorable effect, raising the possibility that the lack of
significance may be attributable to the limited sample size. In contrast, no
prognostic value of KELIM score was observed in patients with mucinous
carcinomas. This finding is not entirely unexpected, as this sub-type is known
to have a poor correlation with CA125 kinetics and generally displays limited
chemosensitivity. Furthermore, the survival outcomes of early-stage mucinous
cases in our cohort were less favorable than generally expected, suggesting
that some gastro-intestinal tumors might have been misclassified. This limits
drawing reliable conclusions about this group.

**Results in the Context of Published Literature**

Early-stage epithelial ovarian cancers are under-represented in clinical trials and require better prognostic stratification to personalize adjuvant disease management. While these results confirm the favorable prognosis of early-stage epithelial ovarian cancer (5-year overall survival rate ~ 80%),⁷,³³,³⁴ the present study also suggests that the assessment of CA125 elimination dynamics using the KELIM score could help further understand the patient prognosis. These outcomes are consistent with those of a previous retrospective analysis of 3 large phase III trials (AGO OVAR-9; AGO OVAR-7; and ICON-7) suggesting that KELIM was an independent prognostic factor of the probability of long-term disease >5 years after first-line treatment, in patients with stage I to II diseases (along with stage III, and stage IV).³⁵ Although patient selection was required in the MAOV database to enable KELIM calculation, owing to the need for sufficient CA125 measurements, the baseline CA125 levels of the selected patients were comparable to those reported in previous independent and contemporary cohorts, supporting the representativeness of the database.³⁶,³⁷

**Strengths and Weaknesses**

The present study has several limitations. Although this is an individual pa-
tient-data meta-analysis, its retrospective nature introduces the potential for
interpretation biases. Moreover, as all patients received adjuvant chemo-
therapy, the absence of a control group without chemotherapy precluded
assessment of KELIM predictive value for chemotherapy benefit and prevented
differentiation between true chemosensitivity and post-operative fluctuations
in CA125 elimination dynamics. In addition, data on tumor grade (low-grade vs
high-grade) and FIGO stage sub-classes (IA, IB, IC, IIA, and IIB) were not
available. Similarly, the post-operative residual lesion size was only available
in the binary format of <1 cm versus ≥1 cm. Since true FIGO stage I-II tumors
are expected to be completely resected, cases reported with residual disease
≥1 cm were likely misclassified as early-stage. To ensure a homogeneous
study population and minimize selection bias, we restricted our analysis to
patients reported as having undergone "optimal" carcinologic staging surgery.
In contrast, the historical nature of the clinical trials included in this analysis
may not fully reflect current surgical practice. In particular, the definition of
optimal cytoreduction was based on the historical threshold of 1 cm, whereas
this cut-off has since evolved into contemporary standards. Another point to
consider is that the JGOG-3017 study included patients with clear cell

carcinomas only, which represented 34.7% of the whole population of this
ancillary analysis, including 85.1% with FIGO stage I diseases, which might
explain the lack of prognostic value of FIGO stage regarding overall survival.

Nevertheless, this is, to our knowledge, the largest database of early-stage
epithelial ovarian carcinomas and the first to demonstrate the independent
prognostic value of the KELIM score in patients with optimally resected early-
stage non-mucinous ovarian cancers.

**Implications for Practice and Future Research**

Even after optimal surgery for localized disease followed by adjuvant
chemotherapy (often presented as a curative strategy) patients with an un-
favorable KELIM score experienced unexpectedly poor outcomes. At 5 years,
the relapse risk was 60.5% for patients with serous carcinoma and 39.3% for
those with clear cell carcinoma, while their risks of death were 30.5% and
30.6%, respectively. These findings suggest that patients with unfavorable
KELIM scores may benefit from closer monitoring and/or intensified treatment
strategies, whereas those with favorable KELIM scores might require less
frequent follow-up, if our data were confirmed. The availability of KELIM
calculations through the online tool https://www.biomarker-kinetics.org facil-
itates the identification of these high-risk patients in routine clinical practice.
Prospective validation of these hypotheses is warranted to confirm these
findings and optimize patient management.

CONCLUSIONS

Assessing the KELIM score in patients with non-mucinous FIGO stages I and II
epithelial ovarian carcinoma optimally resected could be of interest for esti-
mating the risk of recurrence and death, particularly in serous and clear cell
carcinomas. This easily measurable indicator could assist in identifying pa-
tients who might benefit from closer surveillance or intensified treatment
strategies.

Author Affiliations

ªClaude Bernard University Lyon 1, Faculty of Medicine Lyon-Sud, Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA UCBL/HCL 3738, Lyon, France

ᵇGINECO, CHU de Saint-Etienne, Institut de Cancérologie et d'Hématologie Universitaire de Saint-Etienne, Medical Oncology, France

ᶜGINECO, GINEGEPS, Centre Hospitalier Lyon-Sud, CITOHL, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Medical Oncology, Lyon, France

⁴Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan

⁵University of Glasgow, UK and School of Cancer Sciences, NHS Greater Glasgow and Clyde, Beatson West of Scotland Cancer Centre, Glasgow, UK

¹Imperial College London, Department of Surgery and Cancer, London, UK

⁹MRC Clinical Trials Unit at UCL, London, UK

¹⁰Nordic Society of Gynaecological Oncology, Copenhagen, Denmark

¹Copenhagen University Hospital, Rigshospitalet, Department of Oncology, Copenhagen, Denmark

¹Norwegian Radium Hospital, Oslo, Norway

²BC Cancer-Vancouver, Vancouver, Canada

¹London Health Sciences Centre, London, ON, Canada

³Inserm U1290 Claude Bernard University Lyon 1 GINECO, Centre Léon Bérard, Lyon, France

⁴Laboratoire Reshape U1290 Inserm-UCBL, Lyon, France

⁵Université Paris-Saclay, Office of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, France

⁶Inserm, Université Paris-Saclay, CESP U1018, Oncostat, labeled Ligue Contre le Cancer, Villejuif, France

⁷University of Glasgow, Institute of Cancer Sciences, Cancer Research UK Clinical Trial Unit, Glasgow, UK

⁸Institut Curie, St Cloud, France

⁹The Jikei University School of Medicine, Tokyo, Japan

**Funding** This work was supported by the Gynecologic Cancer Intergroup (GCIG), the Groupe d'Investigateurs National des Etudes des Cancers Ovariens et du sein (GINECO), the University Claude Bernard, Lyon 1, and the Hospices Civils de
Lyon. No funding bodies had any role in study design, data collection, analysis, interpretation, decision to publish, or preparation of the manuscript.

**Author Contributions** The study was conceptualized by B.Y., R.G., O.C., and X.P. Methodology and formal analysis were conducted by P.C., O.C., and X.P. Data curation was performed by R.G., A.C., E.K., C.K., and X.P. The investigation was carried out by T.K., R.G., I.McN., M.M., K.L., A.T., S.W., I.R.C., L.L., and N.Y. Supervision was provided by B.Y., F.S., O.C., and J.P. P.C. prepared the original draft. All authors contributed to the review and editing of the manuscript and approved the final version.

**Declaration of Competing Interests** PC: Advisory/consulting fees from GSK; support for attending meetings and/or travel from AstraZeneca, Daiichi-Sankyo, Novartis, Roche, and Pfizer.

RG: Investigator-initiated grant from Clovis Oncology; personal consulting fees from Clovis Oncology and GSK and Pharma&; institutional consulting fees from Novartis; honoraria for lectures, presentations, or educational events from AstraZeneca, Clovis Oncology and GSK; support for attending meetings and/or travel from GSK, AbbVie and MSD; participation on a data safety monitoring board or advisory board for the MATAO trial; receipt of donated drugs from GSK; chair of the Scottish Gynaecological Cancer Trials Group, the IGCS Patient Advocacy Group, and the GCIG Pragmatic Trials Working Group; and serving as site principal investigator for trials sponsored by Allarity Therapeutics, AstraZeneca, GSK, ImmunoGen/AbbVie, Novartis, and Verastem Oncology.

IMCN: Consulting fees from AstraZeneca; GSK; BioNTech; Roche, Clovis Oncology, Pharma&; OncoC4; Honoraria for lectures from GSK and Pharma&. Institutional grant support from AZ.

IRC: Honoraria (personal) from Agenus, Blueprint, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Macrogenics, Tesaro and Clovis; Honoraria (institution) from GSK, MSD, Roche and BMS; Advisory/consulting fees from AbbVie, Agenus, Advaxis, BMS, ESAÍ, Daichi, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; research grant/funding (self) from MSD, Roche and BMS; Research grant/ funding (institution) from MSD, Roche, BMS, Novartis, AstraZeneca and Merck Sereno; Travel support from Roche, MSD, AstraZeneca, and GSK. Given her role as a member of the editorial committee of the International Journal of Gynecological Cancer, Isabelle Ray-Coquard was not involved in the peer-review of this article, and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to another journal editor.

The other authors declare no potential conflicts of interest.

**Appendix A. Supplementary data** Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijgc.2025.102719.

## REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. *CA Cancer J Clin.* 2017;67(1): 7–30. https://doi.org/10.3322/caac.21387.

2. Collinson F, Qian W, Fossati R, et al. Optimal treatment of early-stage ovarian cancer. *Ann Oncol.* 2014;25(6):1165–1171. https://doi.org/10.1093/annonc/ mdu116.

3. Ledermann JA, Matias-Guiu X, Amant F, et al. ESGO–ESMO–ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease. *Ann Oncol.* 2024;35(3):248–266. https://doi.org/10.1016/j.annonc.2023.11.015.

4. Upadhyay A, Garg V, Mathur S, et al. Early-Stage epithelial ovarian cancer: predictors of survival. *Gynecol Oncol Rep.* 2022;44:101083. https://doi.org/10.1016/ j.gore.2022.101083.

5. Colombo N, Pecorelli S. What have we learned from ICON1 and Action? *Int J Gynecol Cancer.* 2003;13(suppl 2):140–143. https://doi.org/10.1111/j.1525- 1438.2003.13366.x.

6. Eiriksson LR, Reade CJ, Lennox G, et al. Ovarian cancer distribution of histology, stage, and screening performance. *J Clin Oncol.* 2013;31(suppl 15). https://doi.org/ 10.1200/jco.2013.31.15_suppl.5543, 5543–5543.

7. Trimbos JB, Parmar M, Vergote I, et al. International Collaborative Ovarian neoplasm trial 1 and Adjuvant ChemoTherapy in Ovarian neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. *J Natl Cancer Inst.* 2003;95(2):105–112. https://doi.org/ 10.1093/jnci/95.2.105.

8. Lawrie TA, Winter-Roach BA, Heus P, Kitchener HC. Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. *Cochrane Database Syst Rev.* 2015;2015(12):CD004706. https://doi.org/10.1002/14651858.CD004706. pub5.

9. Colombo N, Sessa C, Bois AD, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and

advanced stages, borderline tumours and recurrent disease. *Int J Gynecol Cancer.* 2019;29(4):728–760. https://doi.org/10.1136/ijgc-2019-000308.

10. You B, Freyer G, Gonzalez-Martin A, et al. The role of the tumor primary chemosensitivity relative to the success of the medical-surgical management in patients with advanced ovarian carcinomas. *Cancer Treat Rev.* 2021;100:102294. https://doi.org/10.1016/j.ctrv.2021.102294.

11. Lauby A, Colomban O, Corbaux P, et al. The increasing prognostic and predictive roles of the tumor primary chemosensitivity assessed by CA-125 elimination rate constant K (KELIM) in ovarian cancer: a narrative review. *Cancers.* 2021;14(1):98. https://doi.org/10.3390/cancers14010098.

12. Corbaux P, You B, Glasspool RM, et al. Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first-line before poly (ADP-ribose) polymerase inhibitor era: a Gynaecologic Cancer Intergroup meta-analysis. *Eur J Cancer.* 2023;191:112966. https://doi.org/10.1016/j. ejca.2023.112966.

13. Paoletti X, Lewisy LA, Daniele G, et al. Assessment of progression-free survival as a surrogate end point of overall survival in first-line treatment of ovarian cancer: a systematic review and meta-analysis. *JAMA Netw Open.* 2020;3(1):e1918939. https://doi.org/10.1001/jamanetworkopen.2019.18939.

14. Hoskins P, Vergote I, Cervantes A, et al. Advanced ovarian cancer: phase III randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel vs carboplatin-paclitaxel. *J Natl Cancer Inst.* 2010;102(20):1547–1556. https://doi.org/ 10.1093/jnci/djg362.

15. Katsumata N, Yasuda M, Isonishi S, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. *Lancet Oncol.* 2013;14(10): 1020–1026. https://doi.org/10.1016/S1470-2045(13)70363-2.

16. Sugiyama T, Okamoto A, Enomoto T, et al. Randomized Phase III trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first-line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG trial. *J Clin Oncol.* 2016;34(24): 2881–2887. https://doi.org/10.1200/JCO.2016.66.9010.

17. Ray-Coquard I, Paraiso D, Guastalla JP, et al. Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group. *Br J Cancer.* 2007;97(9):1200–1205. https://doi.org/ 10.1038/sj.bjc.6604026.

18. Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. *Lancet Oncol.* 2015;16(8):928–936. https://doi.org/10.1016/S1470-2045(15)00086-8.

19. Lindemann K, Christensen RD, Vergote I, et al. First-line treatment of advanced ovarian cancer with paclitaxel/carboplatin with or without epirubicin (TEC versus TC)—a gynecologic cancer intergroup study of the NSGO, EORTC GCG and NCIC CTG. *Ann Oncol.* 2012;23(10):2613–2619. https://doi.org/10.1093/annonc/ mds060.

20. Vasey PA, Jayson GC, Gordon A, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. *J Natl Cancer Inst.* 2004;96(22):1682–1691. https://doi.org/10.1093/ jnci/djh323.

21. Banerjee S, Rustin G, Paul J, et al. A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG. *Ann Oncol.* 2013;24(3):679–687. https://doi.org/10.1093/ annonc/mds494.

22. Colomban O, Tod M, Leary A, et al. Early modeled longitudinal CA-125 kinetics and survival of ovarian cancer patients: a GINECO AGO MRC CTU study. *Clin Cancer Res.* 2019;25(17):5342–5350. https://doi.org/10.1158/1078-0432.CCR- 18-3335.

23. You B, Colomban O, Heywood M, et al. The strong prognostic value of KELIM, a model-based parameter from CA 125 kinetics in ovarian cancer: data from Calypso trial (a GINECO-GCIG study). *Gynecol Oncol.* 2013;130(2):289–294. https://doi.org/ 10.1016/j.ygyno.2013.05.013.

24. Gleiss A, Oberbauer R, Heinze G. An unjustified benefit: immortal time bias in the analysis of time-dependent events. *Transpl Int.* 2018;31(2):125–130. https://doi. org/10.1111/tri.13081.

25. Beal S, Boeckmann A, Bauer R, et al. NONMEM User's Guides (1989-2009). Icon Development Solutions; 2009.

26. Bauer RJ. NONMEM tutorial Part II: Estimation methods and advanced examples. *CPT Pharmacometrics Syst Pharmacol.* 2019;8(8):538–556. https://doi.org/ 10.1002/psp4.12422.

27. You B, Robelin P, Tod M, et al. CA-125 ELIMination rate constant K (KELIM) is a marker of chemosensitivity in patients with ovarian cancer: results from the phase II CHIVA trial. *Clin Cancer Res.* 2020;26(17):4625–4632. https://doi.org/10.1158/ 1078-0432.CCR-20-0054.

28. Colomban O, Tod M, Peron J, et al. Bevacizumab for newly diagnosed ovarian cancers: best candidates among high-risk disease patients (ICON-7). *JNCI Cancer Spectr.* 2020;4(3):pkaa026. https://doi.org/10.1093/jncics/pkaa026.

29. Colomban O, Clamp AR, Cook A, McNeish IA, You B. Benefit from fractionated dose-dense chemotherapy in patients with poor prognostic ovarian cancer: ICON-8 trial. *JCO Clin Cancer Inform.* 2023;7:e2200188. https://doi.org/10.1200/CCI.22.00188.
30. You B, Sehgal V, Hosmane B, et al. CA-125 KELIM as a potential complementary tool for predicting veliparib benefit: an exploratory analysis from the VELIA/GOG-3005 study. *J Clin Oncol.* 2023;41(1):107–116. https://doi.org/10.1200/JCO.22.00430.

31. Shu CA, Zhou Q, Jotwani AR, et al. Ovarian clear cell carcinoma, outcomes by stage: the MSK experience. *Gynecol Oncol.* 2015;139(2):236–241. https://doi.org/10.1016/j.ygyno.2015.09.016.

32. Zhu J, Jiang L, Wen H, Bi R, Wu X, Ju X. Prognostic value of serum CA19-9 and perioperative CA-125 levels in ovarian clear cell carcinoma. *Int J Gynecol Cancer.* 2018;28(6):1108–1116. https://doi.org/10.1097/IGC.0000000000001293.

33. Colombo N, Guthrie D, Chiari S, et al. International Collaborative Ovarian neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. *J Natl Cancer Inst.* 2003;95(2):125–132. https://doi.org/10.1093/jnci/95.2.125.

34. Swart AC. Long-term follow-up of women enrolled in a randomized trial of adjuvant chemotherapy for early stage ovarian cancer (ICON1). *J Clin Oncol.* 2007;25(suppl 18). https://doi.org/10.1200/jco.2007.25.18_suppl.5509, 5509-5509.

35. You B, Van Wagensveld L, Tod M, et al. Low probability of disease cure in advanced ovarian carcinomas before the PARP inhibitor era. *Br J Cancer.* 2022;127(1):79–83. https://doi.org/10.1038/s41416-022-01732-7.

36. Mury D, Woelber L, Jung S, et al. Prognostic and predictive relevance of CA-125 at primary surgery of ovarian cancer. *J Cancer Res Clin Oncol.* 2011;137(7):11311137. https://doi.org/10.1007/s00432-011-0977-1.

37. Nossov V, Amneus M, Su F, et al. The early detection of ovarian cancer: from traditional methods to proteomics. Can we really do better than serum CA-125? *Am J Obstet Gynecol.* 2008;199(3):215–223. https://doi.org/10.1016/j.ajog.2008.04.009.