Measure of CA-125 Elimination May Guide Interval Debulking Surgery Selection in High-Grade Serous Ovarian Cancer

According to results from a single-institution retrospective Korean study of patients with clinical stage III to IV high-grade serous ovarian cancer, serial measurement of CA-125 provided evidence for omission of interval debulking surgery (IDS) in patients who received neoadjuvant chemotherapy.¹

In patients whose calculated CA-125 ELIMination of Rate Constant K (KELIM) value was high, there was no statistically significant benefit to the addition of IDS to neoadjuvant chemotherapy. KELIM, a longitudinal measure of CA-125, is a marker for chemosensitivity, with a higher measure correlated with a greater rate of decline or elimination.

“In those with low KELIM, radiologic complete or partial response by interval debulking surgery or over 6 cycles of chemotherapy are crucial for improving survival due to lower chemosensitivity,” Soo Jin Park, MD, of the Department of Obstetrics and Gynecology at Seoul National University Hospital, Republic of Korea, said in a presentation of that data at the 2022 Annual Global Meeting of the International Gynecologic Cancer Society. “In those with high KELIM, chemotherapy only without interval debulking surgery can be considered with comparable prognosis to neoadjuvant chemotherapy followed by surgery due to higher chemosensitivity.”

KELIM was first described in a 2013 paper by Benoit You, MD, PhD, and colleagues in which patients with recurrent ovarian cancer were examined to evaluate time-change components during chemotherapy.² The investigators concluded that the use of this measure in routine practice may help predict the value of chemotherapy to progression free survival (PFS), and these conclusions have been backed by subsequent studies.^3,4

The current analysis evaluated 279 patients diagnosed from 2000 to 2021 who received neoadjuvant chemotherapy with or without IDS. Those who had stage I or II disease, primary debulking surgery, insufficient follow-up of less than 6 months, insufficient recording of CA-125, or history of PARP inhibitors or antiangiogenic agents were not included. Patients were stratified by KELIM score and had received either chemotherapy without IDS (n = 61) or IDS followed by adjuvant chemotherapy (n = 194).

The selected cutoff KELIM score after 1 cycle of chemotherapy was 0.95. in the chemotherapy alone cohort, more patients had a low vs high KELIM score (59.0% vs 41.0%); the same was true in the group receiving IDS (66.5% vs 33.5%). Of note, patients in the IDS group had a higher median age (P = .098), a higher rate of stage IV disease (64.4% vs 55.7%; P = .221), and received more cycles of chemotherapy (8 [range, 4-15 vs 6 [range, 3-10]; P = .002) vs those in the chemotherapy alone group. The IDS group was mostly comprised of patients with ovarian tumors (92.8%) whereas the chemotherapy only group was dominated by those with genital tract (52.5%) and ovarian (42.6%) tumors (P < .001).

When comparing high (n = 90) vs low (n = 165) KELIM groups, R0/R1 resection rates occurred in 70.0% vs 65.5% of patients, respectively, and R2 in 2.2% vs 12.7%; chemotherapy alone was given in 27.8% vs 21.8% (P = .035). The rate of complete response (CR) in the high KELIM group was 80.6% vs 71.6% in the low KELIM group. Corresponding rates of partial response were 16.5% and 21.6%, with stable or progressive disease occurring in 2.9% and 6.8% (P = .183). There was no difference in the number of chemotherapy cycles by KELIM score (P = .463).

In the low KELIM group, the median PFS was 17.5 months with chemotherapy/IDS vs 11.7 months with chemotherapy alone (P <.001). In those with a high KELIM score, there was a nonsignificant numerical PFS benefit to IDS vs chemotherapy alone at 18.2 months vs 13.8 months (P = .229). Regarding overall survival (OS), there was a clear benefit of IDS plus chemotherapy in those with a low KELIM score at 58.6 months vs 31.7 without IDS (P <.001). However, this benefit did not extend to those with a high KELIM score (55.5 months vs 46.7 months; P = .744).

Further stratifying outcomes by optimal (R0/R1) vs suboptimal (R2) debulking, the low KELIM group continued to show a benefit of IDS for both PFS (P <.001) and OS (P <.001). However, this same correlation was not seen in those with a high KELIM score for either PFS (P = .071) or OS (P = .016).

By multivariate analysis, receipt of more than 6 cycles of chemotherapy was associated with better PFS (HR, 0.684; P = .002) and OS (HR, 0.536; P = .007) in the low KELIM group, whereas the same was not seen for those with high KELIM. Importantly, use of chemotherapy alone was not associated with either poor PFS (HR, 1.432; P = .177) or OS (HR, 0.851; P = .634).

When incorporating radiologic response to chemotherapy, survival was found to be associated with the achievement of either PR or CR regardless of treatment selection in both the high and low KELIM groups.

“This research is consistent with past publications, which shows that the role of maximal cytoreductive surgery affects survival differently according to the KELIM score,” Park said. “Indeed, the extent of maximal cytoreductive surgery largely impacts the low KELIM group, with less impact in the high KELIM group.”

In his distillation of the findings, Dennis S. Chi, MD, Ronald O. Perelman Chair in Gynecologic Surgery, deputy chief of the Gynecology Service, and head of Ovarian Cancer Surgery in the Department of Surgery at Memorial Sloan Kettering Cancer Center in New York, said he agreed with Park and colleagues’ assessment of patients with low KELIM scores, but was skeptical about using a high KELIM score as rationale to forego IDS.

Chi asked, “Since you are applying the KELIM score retrospectively, what were the reasons that you did not operate on those patients with a high KELIM score?” He also wondered whether the high numerical difference in PFS between the IDS and no IDS group for those with a high KELIM score would not be enough to warrant its consideration in this setting. “I’m worried that this would be hard to sell to patients and might lead to [less optimal] results,” he concluded.

References

1. Park SJ, Lee M, Chung HH, et al. Selection criteria for omitting interval debulking surgery after neoadjuvant chemotherapy for advanced high-grade serous carcinoma of the ovary: KGOG OVSURG-2016/SCORE study. Presented at: 2022 Annual Global Meeting of the International Gynecologic Cancer Society; New York, NY; September 29-October 1, 2022. Abstract O004.
2. 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. doi:10.1016/j.ygyno.2013.05.013
3. 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. doi:10.1158/1078-0432.CCR-20-0054
4. 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. doi:10.1158/1078-0432.CCR-18-3335