Epithelial ovarian cancer (EOC) is the gynecological tumor with the highest mortality rate (1). Due to the relatively insidious onset of this disease, approximately 70% of patients were diagnosed with advanced-stage disease (1). BRCA1/2 germline mutations are the strongest known genetic risk factors for EOCs and are found in 6-15% of women diagnosed with that disease. BRCA1/2 carriers with EOCs respond better than non-carriers to platinum-based chemotherapies. This yields greater survival, even though the disease is generally diagnosed at a later stage and higher grade (2). According to the WHO classification of tumors, there are five main histological subtypes of EOC, including high-grade serous, low-grade serous, mucinous, endometrioid, and clear cell carcinoma of the ovary (3). Another rare and highly aggressive type of EOC is ovarian carcinosarcoma, which accounts for less than 5% of ovarian cancer (3). Each of the identified histotypes has distinct clinicopathological and molecular features, and different developmental origins (4). Due to the complexity of histological classification, there are significant differences in the availability and accessibility of treatment options for each subtype, resulting in varying patient outcomes (5). Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway is frequently upregulated in EOC and plays an important role in chemoresistance and preservation of genomic stability, as it is implicated in many processes of DNA replication and cell cycle regulation. The inhibition of the PI3K may lead to genomic instability and mitotic catastrophe through a decrease of the activity of the spindle assembly checkpoint protein Aurora kinase B and consequently increase the occurrence of lagging chromosomes during prometaphase (6).

Ovarian clear cell carcinoma (OCCC) is a rare and unique malignancy of the EOC and has an incidence of 0.6/100,000 (1). The incidence of OCCC in East Asian populations has been increasing, accounting for nearly 30% of EOC (7), while OCCC only accounts for 5-10% in the United States (US) population (8), suggesting that there may be some geographical and ethnic variation in the incidence of OCCC. OCCC is characterized by the presence of clear cells with a hobnail appearance and is often associated with endometriosis (9–11). Moreover, OCCC is known to have distinct clinicopathologic features, genetic alterations, and prognosis compared to other subtypes of EOC (5). OCCC has a unique genetic profile with a lower p53 mutation rate and a lower BRCA1/2 mutation rate but higher mutation rates in AT-rich interaction domain 1A (ARID1A), PIK3CA, and PTEN compared to high-grade serous EOC (12).

Generally, the overall survival (OS) rates for advanced OCCC have been reported to be lower compared to other histological subtypes of EOC (13–15). Despite a lower rate of responses due to intrinsic chemoresistance, the treatment strategy for OCCC is the same used for high-grade serous EOC, which includes aggressive cytoreductive surgery and platinum-based adjuvant chemotherapy. Over the past few decades, there have been significant efforts to improve early detection and develop targeted therapies for EOC (5). Several biological agents have been investigated in patients with newly diagnosed, persistent, or recurrent OCCC, and bevacizumab combined with platinum-taxane chemotherapy had a response rate of 63.6% and one-year progression-free survival was 50.5%, suggesting that the addition of bevacizumab to chemotherapy for OCCC could be an important treatment strategy (16, 17). The response rate in those treated with bevacizumab was higher than other biological agents and bevacizumab was approved for the treatment of EOC starting in 2007 (17–19). Survival trends are crucial in assessing the effectiveness of treatment strategies and advancements in medical care for OCCC. However, it is still unclear whether the advancement of treatment strategies will bring survival improvement to OCCC. This study aimed to investigate the changes in ovarian cancer-specific survival (OCSS) and OS of OCCC patients treated consecutively over a 16-year period using a population-based cohort.

OCCC is a distinct type of cancer that has unique features in its occurrence, development, treatment, and prognosis. OCCC has a unique genetic profile with a lower p53 mutation rate (25%) and a lower BRCA1/2 mutation rate (6.3%) but higher mutation rates in ARID1A, PIK3CA, and PTEN compared to high-grade serous EOC. Since inflammatory and epigenetic processes seem to play a predominant role in the pathogenesis of OCCC, immune checkpoint inhibitors, and epigenetic treatment approaches may play an important role in the treatment of these tumor entities (12). In the past, it has not received much attention due to its rarity. However, in recent years, there has been increased interest in researching OCCC, primarily because of its specific clinical characteristics and the varying survival rates observed in early and late-stage patients. In this study, we utilized the SEER database to analyze data of OCCC patients between 2000 and 2015. We aimed to identify any changes in survival trends among OCCC patients over the past decade and explore the influence of different factors on these trends. Our study will enhance the understanding of the disease and provide valuable insights and evidence for future research on treatment modalities.

In this study, we found an increasing trend in the number of OCCC diagnoses between 2000 and 2015 in Asian Americans. Several studies have found that the incidence rate of OCCC in the Asian population is higher than that in the US (22, 23). We should note that those Asian Americans were first-generation immigrants or descendants of immigrants. A previous study conducted in the US identified an increased risk of OCCC among individuals of Asian Pacific Islander ethnicity. However, the study also found that the risk did not significantly vary based on place of birth, indicating that factors such as acculturation or environmental exposure may not strongly influence the association (24). These findings imply that the development of OCCC involves a complex interplay of external and intrinsic factors. The elevated risk observed in Asian Americans may be attributed to genetic predisposition, making it more difficult to modify or mitigate.

Considerable efforts have been made to implement screening programs for early diagnosis of EOC in the general population, but currently, there is no approved strategy (25). This is also reflected economically and cost-effective strategies for early detection and prevention of ovarian cancer have been investigated over the last decade. The cost of treatment per patient with ovarian cancer remains the highest among all cancer types. As an example, the average initial cost in the first year can amount to around US dollar 80,000, whereas the final year cost may increase to US dollar 100,000 (26). The combination of CA125 and transvaginal ultrasound has been explored, but there is limited evidence demonstrating its effectiveness in reducing EOC mortality (27). The number of asymptomatic ovarian masses has increased with the use of prenatal ultrasonography. Among ovarian tumors that complicate pregnancies, approximately 5% are malignant. Currently, surgical intervention is indicated for an ovarian mass over 6 cm in diameter or when symptomatic (28). A recent study also did not support effective screening in average-risk women (29). In our study, we found that approximately 70% of patients had an elevation of CA125, and patients with advanced stage had a higher risk of elevation of CA125, which was similar to the previous studies (30, 31). However, we found a downward trend in patients with distant stage and an upward trend in regional stage. In addition, the overall trend of patients in localized stage was decreasing. There is currently no effective screening strategy for OCCC. Several studies have indicated that the rise in the proportion of OCCC is attributed to increased estrogen exposure and the subsequent rise in rates of endometriosis (9–11). Therefore, further exploration should be conducted to determine whether screening for long-term estrogen exposure and patients with endometriosis can further improve the early diagnosis of OCCC.

Adjuvant chemotherapy using carboplatin and paclitaxel is currently recommended for those with stage IC2 and above (32). However, the role of adjuvant chemotherapy in patients with stage IA to IC disease remains uncertain. The consensus from the European Society for Medical Oncology-European Society of Gynaecological Oncology indicates that adjuvant chemotherapy is not recommended for stage IA, IB, or IC1 OCCC with complete surgical staging (33). A recent SEER study showed that there was no OS benefit for patients with stage IC OCCC receiving adjuvant chemotherapy (5-year OS, 83% vs. 80%, P=0.62) (34). Several small sample studies also found that chemotherapy did not improve the survival of stage I-II OCCC (35, 36). Moreover, a previous study conducted at two tertiary centers in Toronto showed a potential benefit of adjuvant chemotherapy in reducing disease recurrence, although this did not result in an improved OS in stage I-II OCCC (37). In our study, we observed that chemotherapy did not enhance the survival of patients in the localized and regional stages, but the use of chemotherapy improved the survival of patients with distant stage. However, a cohort study conducted using the National Cancer Database demonstrated a benefit in OS for patients with stage I OCCC who received adjuvant chemotherapy (38). Considering the limited conclusive evidence regarding its efficacy in this specific subgroup, the decision to proceed with adjuvant chemotherapy or opt for observation should be personalized after thorough patient counseling.

Several studies have shown that OCCC is considered to be relatively insensitive to chemotherapy compared to other subtypes of EOC. In a study of 27 patients with stage III/IV OCCC and residual disease after surgery, the response rate to platinum-based chemotherapy was only 11.1% (39). Additionally, the response rate to chemotherapy for OCCC patients with recurrent disease was reported to be as low as 6-8% (40). A previous study has found a high probability of ARID1A gene mutation in OCCC (49%), and there is a significant correlation between ARID1A gene mutation and platinum resistance of patients (10). There is also a relationship with the specific tumor microenvironment of OCCC (41–43). Our study found that patients with distant stage receiving surgery and chemotherapy had survival improvement over the years, which may be related to the improvement of chemotherapy regimen methods and exploration of targeted drugs in patients with distant stage OCCC, including the use of bevacizumab in distant stage OCCC. Bevacizumab was approved for the treatment of EOC starting in 2007 and several studies have found that the use of bevacizumab was associated with a higher response rate and better survival outcomes in relapsed or metastatic OCCC (17–19, 44). New chemotherapy regimens, including docetaxel and irinotecan (45), and gemcitabine (46, 47), may improve the treatment sensitivity of platinum-resistant patients. Moreover, the advent of new targeted therapies may further improve patient survival in the future (48).

While OCCC is not as chemosensitive as the more common high-grade serous EOC, there is very limited data regarding the actual clinical benefit of chemotherapy in OCCC patients. Therefore, it is crucial to emphasize the need for novel targeted treatments for the management of OCCC. Several studies have found that OCCC had promising responses to immune checkpoint inhibitors (49–51). Moreover, the combination of immune checkpoint inhibitors and targeting angiogenesis including bevacizumab or lenvatinib also showed clinical benefit in OCCC (52–54). Notch and VEGF are essential in ovarian cancer angiogenesis and Notch has also been related to chemoresistance. Thus, Notch targeting, and mainly dual targeting of Notch and VEGF, is a promising strategy in ovarian cancer. The combination of Notch inhibition with chemotherapy or antiangiogenics showed interesting activity in early-phase clinical studies. Navicixizumab, a dual anti-Dll4 and anti-VEGF in combination with weekly paclitaxel showed a response rate of 43% in heavily pretreated platinum-resistant patients (55). However, we need to note that the survival improvement is not very significant, and the CSS and OS of distant stage patients indicate an improvement of 5% and 5% between 2000 and 2015, respectively. In addition, we should also note that studies on multiple innovative drugs, including cabozantinib (56), temsirolimus (57), and ENMD-2076, did not significantly improve patient survival (58). Therefore, further exploration based on molecular stratification should be needed in the future to optimize treatment strategies for OCCC patients.

Age itself is a poor prognostic factor in patients with EOC (59). Our study also showed better OCSS and OS in those aged <65 years compared to those aged ≥65 years. Our results also demonstrated a significant survival improvement in patients aged <65 years, especially for patients with distant stage. For young patients, there has been little overall change in the survival rates for localized and regional stage diseases over the years, which may be correlated with the overall stability in treatment patterns among these patients over the past years. However, in patients with distant stage, it is possible that more of them have been enrolled in clinical trials for new drugs or have received more aggressive treatments. In those aged ≥65 years, we found no survival improvement over the years, including those with distant stages. The reasons are not fully clarified. Several factors could contribute to the survival difference by different age groups, including comorbidity, more advanced stage at diagnosis, toxic effects of chemotherapy, or that elderly patients are less often treated with optimal surgery or chemotherapy (60). Moreover, in other histotypes of EOC, age is associated with differences in underlying biology. Therefore, there may also be different biological behaviors exhibited among age groups in OCCC. Further studies are needed to investigate the disparities in biological behaviors among age groups in OCCC (61–64). Finally, most clinical trials exclude elderly individuals or have a median age of only around 60 years (65–67). Due to the potential survival benefits inherent in participating in various clinical trials (68), suitable elderly populations should also participate in clinical trials to evaluate the impact of new treatment regimens on patient survival outcomes as much as possible.

Some limitations should be mentioned. First, the retrospective nature of the study, the long duration of the study period, and the use of different therapeutic approaches are inherent biases in the research design. Second, the lack of a centralized pathology review may have resulted in some misclassification of the histological types. High-grade serous EOC with clear cell change has historically been frequently misclassified as OCCC, which would account for some of the trends observed in the study, such as the decrease in distant stage disease diagnoses (69). Third, the SEER database did not record information regarding chemotherapy regimens, chemotherapy cycles, chemotherapy completion rates, targeted therapy, etc. Fourth, information about comorbidities was also not recorded in the SEER database, which might cause bias in the results. Moreover, some of the findings that showed borderline or marginal significance may benefit from long-term follow-up in order to enhance the statistical power. Finally, adjustment for multiple testing was not performed for this study.

In conclusion, our study observed a significant increase in the survival outcomes in OCCC from 2000 to 2015, and patients aged <65 years and those with distant stage experienced a greater improvement in survival.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

As the SEER database consists of de-identified information, the study was exempt from the approval process of the Institutional Review Boards of the First Affiliated Hospital of Xiamen University. The studies were conducted in accordance with the local legislation and institutional requirements.

B-QT: Conceptualization, Data curation, Writing – original draft. S-WW: Conceptualization, Data curation, Formal analysis, Writing – original draft. J-YX: Conceptualization, Data curation, Investigation, Methodology, Writing – review & editing. S-GW: Funding acquisition, Resources, Validation, Visualization, Writing – review & editing. JZ: Conceptualization, Data curation, Investigation, Resources, Visualization, Writing – review & editing.