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. 2024 Sep 12;1(3):31. doi: 10.1097/og9.0000000000000031

Adjuvant Chemotherapy for Stage I Ovarian Clear Cell Carcinoma

Naoki Horikawa 1,✉, Yoshihide Inayama 1, Miki Otsuki 1, Kota Yamauchi 1, Yukako Mizuno 1, Saya Kiyoshige 1, Yukiko Taga 1, Kazuki Yamano 1, Maki Umemiya 1, Motonori Matsubara 1, Yukio Yamanishi 1, Takahito Ashihara 1, Ikuko Emoto 1, Masaki Mandai 1, Kenzo Kosaka 1, Ken Yamaguchi 1, for the KAMOGAWA Study Group
PMCID: PMC12456521  PMID: 41001218

Postoperative platinum-based multiagent chemotherapy was associated with reduced recurrence of stage I ovarian clear cell carcinoma; omission of chemotherapy may not be suitable in these patients.

Abstract

OBJECTIVE:

To assess the association between postoperative chemotherapy and the prognosis of patients with stage I ovarian clear cell carcinoma.

METHODS:

This was a retrospective cohort study of patients with stage I ovarian clear cell carcinoma who underwent surgery, including hysterectomy and bilateral salpingo-oophorectomy, between 2005 and 2019 at 11 affiliated institutions. Patients with preoperative lymph node enlargement, and those who underwent fertility-sparing surgery were excluded. The primary outcome was disease-free survival and overall survival, and was investigated as a secondary outcome. We used propensity score overlap weighting to adjust for confounding factors and estimated the adjusted hazard ratios (HRs) and 95% CIs for the disease-free and overall survival of patients in the control group that did not receive chemotherapy and in the platinum-based multiagent chemotherapy group during the follow-up period.

RESULTS:

In total, 283 patients (64 in the control group and 219 in the chemotherapy group) were included. Five-year disease-free survival was 0.77 (95% CI, 0.66–0.89) in the control group and 0.86 (95% CI, 0.81–0.91) in the chemotherapy group. The unadjusted HR was 0.69 (95% CI, 0.36–1.32; P=.26). After adjustment, patients who received chemotherapy had a significantly lower risk of recurrence than those in the control group (weighted HR for disease-free survival: 0.43; 95% CI, 0.20–0.90; P=.026). There was no difference in overall survival (weighted HR 0.68; 95% CI, 0.27–1.69; P=.40).

CONCLUSION:

Postoperative platinum-based multiagent chemotherapy was associated with improved disease-free survival. These findings provide crucial information for shared decision-making regarding whether to undergo adjuvant chemotherapy.

Globally, epithelial ovarian cancer is the leading cause of death among patients with gynecologic malignancies,1,2 and ovarian clear cell carcinoma accounts for 5–10% of epithelial ovarian cancers. Ovarian clear cell carcinoma is even more prevalent in Asian countries, and its prevalence is increasing.3–5 The standard treatment for advanced epithelial ovarian cancer, including ovarian clear cell carcinoma, consists of cytoreductive surgery and postoperative platinum-based chemotherapy.6,7 However, unlike other subtypes of epithelial ovarian cancer, such as high-grade serous carcinoma and endometrioid carcinoma, ovarian clear cell carcinoma tumors are known for their resistance to chemotherapy, which results in poorer survival outcomes in patients with advanced disease than in patients with other epithelial ovarian cancer subtypes.8–10

The role of postoperative chemotherapy in stage I ovarian clear cell carcinoma is unclear. In some studies, postoperative chemotherapy was observed to improve the outcomes in patients who had a high risk of recurrence.11,12 On the other hand, a large retrospective cohort study reported that postoperative chemotherapy provided no benefit to patients with stage I ovarian clear cell carcinoma.13 We hypothesized that the conflicting outcomes observed in prior studies arose from insufficient control of confounding factors; many studies that focus on stage I ovarian clear cell carcinoma have a greater proportion of patients who did not receive chemotherapy in stage IA, whereas more patients with stage IC received chemotherapy. The answer to this clinical question is highly important because approximately half of all patients with ovarian clear cell carcinoma are diagnosed in the early stages of the disease and at a younger age than patients with other epithelial ovarian cancer subtypes.6,14

To address this concern, we conducted a multicenter retrospective cohort study, adjusting for potential confounders using the propensity score method, to evaluate the association between the adjuvant effect of platinum-based multiagent chemotherapy and the outcomes of patients with stage I ovarian clear cell carcinoma.

METHODS

This was a multicenter retrospective cohort study using the electronic medical records of 11 hospitals in the KAMOGAWA (Kyoto Academy Members of Obstetrics and Gynecology Aiming for Women's Aid) Study Group. The IRB of Shizuoka General Hospital approved the present study (reference number, SGHIRB#2020071).

We included women who underwent surgery for unilateral early-stage ovarian clear cell carcinoma (stage IA and 1C1–3) between January 2005 and December 2019. Patients who underwent two-stage surgery were included unless the interval between the first and second surgeries was more than 3 months or if the first surgery was cystectomy. We excluded women who underwent surgery before the digitization of medical records, those with performance status of 2 or higher, those with preoperative lymph node enlargement (short axis of at least 10 mm, evaluated by computed tomography), and those who underwent fertility-sparing surgery.

Patients in the chemotherapy group and the control group were those who started platinum-based multiagent chemotherapy and those who did not receive any chemotherapy within 3 months after surgery, respectively. For those who had postoperative complications (defined as a Clavien‒Dindo classification grade III or higher),15 this period was set to 4 months. Patients who started chemotherapy other than platinum-based multiagent chemotherapy were excluded.

The primary outcome was disease-free survival, defined as the number of days from the first surgery for ovarian clear cell carcinoma to recurrence. Overall survival was investigated as a secondary outcome. Outcomes within the period up to 10 years postoperatively or until December 2019 were analyzed.

We applied overlap weighting to balance the baseline characteristics between the two groups.16 The propensity score for receiving adjuvant platinum-based multiagent chemotherapy was estimated using a logistic regression model. We added the following variables to the logistic regression model as covariates based on clinical knowledge: patient age, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), comorbidities (diabetes mellitus and cardiovascular disease), use of immunosuppressants, presence of postoperative complications, stage of ovarian clear cell carcinoma, preoperative tumor size (cyst size), adhesion in the pouch of Douglas (an indicator of intra-abdominal adhesions), hospital characteristics, presence of pelvic and para-aortic lymphadenectomy at surgery, and year of surgery. Details on adhesions in the pouch of Douglas were obtained by examining surgical records, and in instances where this information was not documented, preoperative MRI findings were used as an alternative. For hospital characteristics, we evaluated whether the hospitals were Japan Society of Gynecologic Oncology–accredited hospitals, which has been reported to be related to oncologic outcomes in patients with gynecologic malignancies.17 We excluded patients who had missing covariate data and performed a complete case analysis.

The Kaplan–Meier curves were estimated before and after propensity score weighting. To examine the effect of chemotherapy on disease-free survival and overall survival, hazard ratios (HRs), and 95% CIs were calculated using unweighted and overlap-weighted Cox proportional hazards models. The characteristics of the study population were summarized using proportions for categorical variables and means and SDs for continuous variables. We compared the baseline characteristics of the women in each group before and after propensity score–weighted adjustment using a standardized difference, which is not influenced by sample size.18 A standardized difference of more than 0.1 is usually regarded as a meaningful imbalance between the groups. For subgroup analysis, patients were divided into a stage IA group and a stage IC group. In each subgroup, the propensity score was calculated, and the HR and 95% CI of the effect of chemotherapy on disease-free survival and overall survival were calculated using unweighted and overlap-weighted Cox proportional hazards models. The HRs and 95% CIs for the main analysis and subgroup analysis were compared using forest plots. Statistical analysis was performed using R version 4.0.5 (R Foundation, Vienna, Austria).

RESULTS

The study flow chart is presented in Figure 1. In total, 331 women underwent surgery for unilateral early-stage ovarian clear cell carcinoma between January 2005 and December 2019. After excluding those who did not meet the eligibility criteria, 224 patients were included in the chemotherapy group and 65 patients were included in the control group. Five patients in the chemotherapy group (2.2%) and one patient in the control group (1.5%) were excluded from the analysis due to missing data. Finally, 219 patients in the chemotherapy group and 64 patients in the control group were analyzed. Of the 219 women in the chemotherapy group, 158 (72.1%) received six cycles of chemotherapy. No patients received neoadjuvant chemotherapy before surgery for ovarian clear cell carcinoma, and among those who were analyzed in the control group, none underwent postoperative chemotherapy 3 months or later after surgery. The details of the chemotherapy regimens in the chemotherapy group are presented in Appendix 2, available online at http://links.lww.com/AOG/D830. Among the 219 women in the chemotherapy group, 184 (84.0%) received paclitaxel and carboplatin therapy, with paclitaxel-carboplatin therapy every 3 weeks being most common, constituting 62.1% of the chemotherapy regimens.

Fig. 1. Selection of the study samples. *Stages IA, IC1, IC2, and IC3. OCCC, ovarian clear cell carcinoma; PS, performance status.

Fig. 1.

Horikawa. Adjuvant Chemotherapy in Stage I OCCC. O&G Open 2024.

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The baseline characteristics of the patients in each group before and after propensity score–weighted adjustment are shown in Table 1. Before the adjustment, the mean age of the patients was 57.4 years in the control group and 55.1 years in the chemotherapy group. The standard differences were greater than 0.1 for age, diabetes status, stage (IA, 1C1, and 1C3), preoperative cyst size, Japan Society of Gynecologic Oncology–accredited hospital status, pelvic lymphadenectomy status, and year of surgery, indicating that these factors were not evenly distributed between the two groups. Notably, although 65.6% of patients with stage IA ovarian clear cell carcinoma were in the control group, 21.9% were in the chemotherapy group. After adjustment, both groups included 50.4% of patients with stage IA ovarian clear cell carcinoma, 29.6% of patients with stage IC1 ovarian clear cell carcinoma, 14.6% of patients with stage IC2 ovarian clear cell carcinoma, and 5.4% of patients with stage IC3 ovarian clear cell carcinoma.

Table 1.

Baseline Characteristics Before and After Propensity Score–Weighting Adjustment

Characteristic Before Adjustment After Adjustment
Control Group (n=64) Chemotherapy Group (n=219) Standardized Difference Control Group (n=36.2) Chemotherapy Group (n=36.2) Standardized Difference
Age (y) 57.4±11.8 55.1±10.4 0.206 55.9±11.3 55.9±11.0 <0.001
BMI (kg/m2) 22.0±3.7 22.0±3.4 0.005 22.2±4.0 22.2±3.4 <0.001
Diabetes mellitus 5 (7.8) 6 (2.7) 0.228 2.3 (6.4) 2.3 (6.4) <0.001
Cardiovascular diseases 6 (9.4) 15 (6.8) 0.093 3.1 (8.5) 3.1 (8.5) <0.001
Use of immunosuppressant 2 (3.1) 5 (2.3) 0.052 1.1 (2.9) 1.1 (2.9) <0.001
Postoperative complications 4 (6.2) 14 (6.4) 0.006 2.0 (5.5) 2.0 (5.5) <0.001
Stage 1A 42 (65.6) 48 (21.9) 0.981 18.2 (50.4) 18.2 (50.4) <0.001
Stage 1C1 13 (20.3) 106 (48.4) 0.619 10.7 (29.6) 10.7 (29.6) <0.001
Stage 1C2 7 (10.9) 24 (11.0) 0.001 5.3 (14.6) 5.3 (14.6) <0.001
Stage 1C3 2 (3.1) 41 (18.7) 0.516 1.9 (5.4) 1.9 (5.4) <0.001
Preoperative cyst size (cm) 12.9 (6.0) 12.3 (5.7) 0.107 13.0 (5.9) 13.0 (5.8) <0.001
Adhesions in pouch of Douglas 39 (60.9) 124 (56.6) 0.088 21.6 (59.7) 21.6 (59.7) <0.001
JSGO-accredited hospitals 44 (68.8) 106 (48.4) 0.422 21.8 (60.4) 21.8 (60.4) <0.001
Pelvic lymphadenectomy 45 (70.3) 167 (76.3) 0.135 25.9 (71.6) 25.9 (71.6) <0.001
Para-aortic lymphadenectomy 41 (64.1) 135 (61.6) 0.05 22.6 (62.5) 22.6 (62.5) <0.001
Year of surgery 2012 2013 0.256 2012 2012 <0.001
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BMI, body mass index; JSGO, Japan Society of Gynecologic Oncology.

Data are mean±SD or n (%) unless otherwise specified.

During the observation period, 13 (20.3%) patients in the control group and 29 (13.2%) patients in the chemotherapy group developed a recurrence. The median (interquartile range) follow-up duration was 56.4 (26.2, 91.1) months in the control group and 52.6 (18.7, 84.4) months in the chemotherapy group. The Kaplan–Meier curve for disease-free survival before propensity score weighting in women with ovarian clear cell carcinoma in the two groups is presented in Figure 2A. In the control group, the 3- and 5-year disease-free survival rates were 0.88 (95% CI, 0.80–0.97) and 0.77 (95% CI, 0.66–0.89), respectively. In the chemotherapy group, the 3- and 5-year disease-free survival rates were 0.86 (95% CI, 0.81–0.91) and 0.86 (95% CI, 0.81–0.91), respectively. The unadjusted HR before the propensity score–weighted adjustment was 0.69 (95% CI, 0.36–1.32, P=.26).

Fig. 2. Kaplan-Meier curves of disease-free survival for the two groups before (A) and after (B) propensity score weighting. The unadjusted and adjusted hazard ratios were 0.69 (95% CI, 0.36–1.32; P=.26) and 0.43 (95% CI, 0.20–0.90; P=.026), respectively.

Fig. 2.

Horikawa. Adjuvant Chemotherapy in Stage I OCCC. O&G Open 2024.

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The propensity score–weighted Kaplan–Meier curve is presented in Figure 2B. In the control group, the 3- and 5-year disease-free survival rates were 0.86 (95% CI, 0.77–0.97) and 0.76 (95% CI, 0.64–0.90), respectively. In the chemotherapy group, the 3- and 5-year disease-free survival rates were 0.90 (95% CI, 0.85–0.95) and 0.90 (95% CI, 0.85–0.95), respectively. The HR after the adjustment was 0.43 (95% CI, 0.20–0.90; P=.026).

During the observation period, there were eight deaths (12.5%) in the control group and 23 deaths (10.5%) in the chemotherapy group. The median (interquartile range) follow-up duration was 56.4 (26.2, 91.1) months in the control group and 52.6 (18.7, 84.6) months in the chemotherapy group. The Kaplan–Meier curves for overall survival before and after propensity score weighting are shown in Figure 3A and B, respectively. Before adjustment, the 3- and 5-year overall survival rates in the control group were 0.91 (95% CI, 0.84–0.99) and 0.84 (95% CI, 0.74–0.95), respectively, and in the chemotherapy group, both were 0.88 (95% CI, 0.83–0.93). The unadjusted and adjusted HRs for overall survival were 0.88 (95% CI, 0.40–1.98; P=.76) and 0.68 (95% CI, 0.27–1.69; P=.40), respectively.

Fig. 3. Kaplan-Meier curves of overall survival for the two groups before (A) and after (B) propensity score weighting. The unadjusted and adjusted hazard ratios for overall survival were 0.88 (95% CI, 0.40–1.98; P=.76) and 0.68 (95% CI, 0.27–1.69; P=.40), respectively.

Fig. 3.

Horikawa. Adjuvant Chemotherapy in Stage I OCCC. O&G Open 2024.

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Appendices 3 and 4, available online at http://links.lww.com/AOG/D830, show the Kaplan–Meier curves for the stage IA and IC groups, respectively. The adjusted HRs for disease-free survival were 0.25 (95% CI, 0.03–2.10; P=.20) in the stage IA group and 0.45 (95% CI, 0.19–1.06; P=.066) in the stage IC group. The adjusted HRs for overall survival were 0.46 (95% CI, 0.05–4.32; P=.50) in the stage IA group and 0.64 (95% CI, 0.23–1.80; P=.40) in the stage IC group. The HRs and 95% CIs for the main analysis and subgroup analysis are presented in Figure 4 using a forest plot. The 95% CIs of both groups overlapped well, and no obvious heterogeneity of effects was identified.

Fig. 4. Forest plots for the adjusted hazard ratios (HRs) of disease-free survival (A) and overall survival (B).

Fig. 4.

Horikawa. Adjuvant Chemotherapy in Stage I OCCC. O&G Open 2024.

Open in a new tab

DISCUSSION

In this multicenter retrospective cohort study of patients with stage I ovarian clear cell carcinoma, we found that postoperative platinum-based multiagent chemotherapy was associated with improved disease-free survival. This study estimates the effectiveness of postoperative chemotherapy in patients with stage I ovarian clear cell carcinoma with adjustment for measurable confounders using propensity score–weighted analysis. This significantly decreased risk of recurrence is meaningful in the decision to administer postoperative chemotherapy.

The effect of postoperative chemotherapy on the recurrence rate of stage I ovarian clear cell carcinoma remains controversial. Consistent with our data, a previous study demonstrated that omission of adjuvant chemotherapy was associated with decreased disease-free survival (stage-adjusted HR 3.3, 95% CI, 1.2–9.6; P=.027) for patients with stage I ovarian clear cell carcinoma.19 Conversely, a recent systematic review and meta-analysis reported no benefit of chemotherapy on disease-free survival in the overall stage I population.20 However, this result stemmed from an analysis that did not account for the disparity in the proportion of patients with stage IA and IC disease between the chemotherapy and chemotherapy-omission groups. In general, the prognosis of stage IC ovarian clear cell carcinoma is poorer than that of stage IA ovarian clear cell carcinoma,9,21,22 possibly due to tumor cell spillage. Therefore, the difference between stage IA ovarian clear cell carcinoma and IC ovarian clear cell carcinoma must be considered when investigating the effects of treatment on stage I ovarian clear cell carcinoma.

Several studies included in the aforementioned meta-analysis reported adjusted HRs of disease-free survival that considered this difference in subclassification of the clinical stage.20 Takano et al reported an adjusted HR of 1.30 (95% CI, 0.16–10.4; P=.80) for postoperative chemotherapy,23 and Takada et al24 reported an adjusted HR of 1.88 (95% CI, 0.61–5.78; P=.27) for omitting postoperative chemotherapy, which is equivalent to an adjusted HR of 0.53 (95% CI, 0.17–1.63) for postoperative chemotherapy. Focusing solely on P values might lead to misunderstandings that our study's results contradict those of previous studies. However, the 95% CIs in these studies included those obtained in our study (adjusted HR 0.43, 95% CI, 0.20–0.90). Therefore, our study's results do not contradict those of previous reports; in previous studies, limited sample sizes and inclusion of numerous variables in Cox regression models relative to events just led to wider CIs and larger P values.

Treatment effects based on subclassification of clinical stage have also been assessed in previous studies. Although several studies have demonstrated the effectiveness of chemotherapy for stage IC ovarian clear cell carcinoma, its effectiveness in stage IA has been called into question.20,24,25 However, these studies that refute the treatment efficacy of chemotherapy in patients with stage IA disease suffer from small sample sizes and are underpowered to draw conclusions24 or extrapolate the overall results in stage I to stage IA without accounting for the difference between stage IA and IC.20 In our study, data limited to patients with stage IA disease were also underpowered; however, as shown in Figure 4, there was no apparent heterogeneity of effect between patients with stage IA and stage IC disease. Given the insufficient evidence on the effect of chemotherapy on disease-free survival in patients with stage IA disease and the lack of apparent heterogeneity in the effect between patients with stage IA and IC disease in our study, we consider it reasonable to extrapolate the treatment effect observed in patients with stage I disease to those with stage IA disease at this point, suggesting an improvement in disease-free survival due to chemotherapy.

When deciding whether to administer chemotherapy to patients with stage I ovarian clear cell carcinoma in clinical practice, it is important to consider that stage IA and IC have different baseline risks of recurrence, resulting in increased number needed to treat (NNT) in stage IA ovarian clear cell carcinoma.26 In other words, 5-year disease-free survival was 0.84 in the control group with stage IA disease but was 0.95 in the chemotherapy group, which means that the NNT was 9.1, indicating that chemotherapy can decrease the number of recurrences for 1 of 9.1 patients. On the other hand, the NNT for stage IC patients was 4.8, which indicates that fewer patients with stage IA disease can avoid recurrence through chemotherapy compared with those with stage IC. Accordingly, omitting chemotherapy may be acceptable in clinical practice for patients with a lower risk of recurrence, such as patients with stage IA disease with confirmed negative lymph nodes on staging lymphadenectomy. In fact, the European Society of Clinical Oncology and National Comprehensive Cancer Network guidelines allow the omission of chemotherapy in patients with stage IA ovarian clear cell carcinoma who undergo staging lymphadenectomy.27,28

Several limitations of this study should be noted. First, although we adjusted for the difference in baseline characteristics between the two groups, the effect of unmeasured confounders cannot be ruled out. Nevertheless, it is noteworthy that for clinically significant confounding factors, including age, stage, presence of diabetes, preoperative cyst size, hospital characteristics, pelvic lymphadenectomy, and year of surgery, there was noticeable heterogeneity in their distribution between the groups before adjustment. After adjustment, however, a commendable balance was achieved between the two groups in terms of these important factors, which were not considered in previous studies, and we believe this enables a valid comparison. Second, no significant difference in overall survival was observed between the two groups even after adjustment. The relatively wide CI of the adjusted HR for overall survival (95% CI, 0.27–1.69) suggests the possibility of being underpowered. Therefore, based on the results of this study, it is inconclusive whether adjuvant chemotherapy extends overall survival. Indeed, the effect of postoperative chemotherapy on overall survival is as controversial as its effect on disease-free survival.19,20,29 Further evaluation of overall survival in larger studies is warranted. Third, this study included patients who did not undergo staging lymphadenectomy. However, we excluded patients with lymphadenopathy on imaging. Moreover, this did not affect the comparison of the effectiveness of chemotherapy because we controlled for the percentage of patients who underwent lymph node dissection.

The Japanese Gynecologic Oncology Group 3,020 trial, a randomized phase III trial of adjuvant chemotherapy in patients with stage I epithelial ovarian cancer who underwent staging surgery, is ongoing.30 The primary endpoint of that clinical trial is overall survival, and the results are awaited. In conclusion, this study found an association between postoperative platinum-based multiagent chemotherapy and reduced or delayed recurrence of stage I ovarian clear cell carcinoma. Although the toxicity of chemotherapy should be monitored carefully, omission of chemotherapy may not be suitable in patients with stage I disease. We believe our findings provide crucial information for shared decision-making regarding whether to undergo adjuvant chemotherapy. The treatment effect of chemotherapy in patients with stage IA ovarian clear cell carcinoma and the treatment effect on overall survival in patients with stage I ovarian clear cell carcinoma need to be confirmed in larger studies.

Footnotes

Financial Disclosure The authors did not report any potential conflicts of interest.

The authors sincerely thank Dr. Kentaro Ishida and Dr. Mitsuru Tsuji for collaborating with the data collection.

Each author has confirmed compliance with the journal's requirements for authorship.

*

A list of hospitals in the KAMOGAWA (Kyoto Academy Members of Obstetrics And Gynecology Aiming For Women’s Aid) Study Group is available in Appendix 1 online, http://links.lww.com/AOG/D830.

Peer reviews and author correspondence are available at http://links.lww.com/AOG/D831.

Naoki Horikawa and Yoshihide Inayama contributed equally to this work.

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