Introduction
Epithelial ovarian cancer (EOC) is considered as one of the most lethal diseases among gynecologic malignancies. Approximately 63% of patients were diagnosed with advanced stage of this disease at initial diagnosis, accounting for 27% of the five-year survival rate according to the Cancer Statistic in USA (2012) [
1]. According to the guideline issued by the International Federation of Gynecology and Obstetrics (FIGO) in 2000, patients with ovarian cancer and exhibiting appropriate medical conditions should undergo primary surgery to remove tumors completely. Following surgery, the standard treatment is at least six cycles of platinum/taxane chemotherapy for advanced diseases; three to six cycles are required for early diseases unless the patients are diagnosed with low-risk early cancer [
2]. Such a standard treatment strategy was supported by the NCCN guideline in 2012 [
3]. However, the five-year survival rate of patients with advanced EOC remains unchanged. Several factors influence the prognosis of patients with ovarian cancer. These factors include age, stage, histological type and grade, post-operative residual implant size, and initial tumor volume.
To date, limited information is available regarding the final outcomes of Chinese patients with EOC subjected to first-line treatment. We reported the long-term clinical outcomes of 251 Chinese patients with EOC and subjected to initial surgery followed by platinum-based chemotherapy. Several prognostic factors in relation to patient outcomes were retrospectively analyzed.
Materials and methods
Patients and clinico-pathological data
The clinico-pathological data of 251 patients with primary EOC were obtained from the Gynecology Department in Women’s Hospital, School of Medicine, Zhejiang University. These patients underwent primary debulking surgery followed by three to six courses of platinum-based combination chemotherapy for early disease and at least six courses for advanced diseases at our institution from January 2002 to December 2008. Chemotherapy regimens included cisplatin/carboplatin and cyclophosphamide (PC), cisplatin/carboplatin, adriamycin, and cyclophosphamide (PAC), and paclitaxel and cisplatin/carboplatin (TP). Patients who were not diagnosed with primary EOC, received uncompleted courses of chemotherapy, did not receive chemotherapy, or showed incomplete clinico-pathological data were excluded from this study. All of the patients were followed up by an interview in the clinic or through the telephone. The following data were obtained: patient age; FIGO stage; histological type; tumor grade; pre-operative maximum tumor diameter; debulking status; serum CA125 level; and recurrence or death date.
Statistical analysis
Chi-square test was performed using SPSS 16.0 for Windows. Multivariate Cox regression model was performed to identify the independent risk factors associated with patient survival. A level of 0.05 indicated statistical significance. All of the reported P values were bilateral.
Results
Patients’ clinical and pathological characteristics
The clinico-pathological characteristics of the 251 patients included in this study are summarized in Table 1. The median age at the time of diagnosis was 51 years, ranging from 19 years to 89 years. Patients were recruited according to the FIGO classification: 50 patients with stage I EOC (19.9%); 38 patients with stage II EOC (15.1%); 147 patients with stage III EOC (58.6%); and 16 patients with stage IV (6.4%) EOC. Among these patients, 74.5% (187/251) were optimally debulked and 25.5% (64/251) were suboptimally debulked. The most common histopathology was serous carcinoma (46.6% or 117/251). The histological grading was well differentiated (8.0% or 20/251), moderate (20.3% or 51/251), poorly (62.5% or 157/251), and unaware (9.2% or 23/251). The median follow-up from the end of initial treatment to June 2010 was 58 months (range 8–99).
Survival of patients with EOC
Among the 251 patients, 94 patients died and 157 patients survived. The three-year progression-free survival (PFS) rate was 61.7% for FIGO I–II, 19.9% for FIGO III–IV, and 33.9% for all stages. By comparison, the five-year PFS rate was 44.6% for FIGO I–II, 17.7% for FIGO III–IV, and 28.3% for all stages. The three-year overall survival (OS) rate was 67.9% for FIGO I–II, 41.7% for FIGO III–IV, and 50.2% for all stages. The five-year OS rate was 52.7% for FIGO I–II, 30.8% for FIGO III–IV, and 39.2% for all stages.
Factors associated with the prognosis of patients with EOC
Tables 2 and 3 showed the association of PFS and OS with the clinico-pathological parameters evaluated by univariate and multivariate analyses. Univariate analysis results revealed that advanced FIGO stage, serum CA125, and suboptimal debulking were significant factors of PFS and OS. In multivariate analysis, PFS was significantly influenced by FIGO stage and suboptimal debulking. However, OS was significantly influenced by advanced FIGO stage only.
Discussion
The standard primary treatment for EOC involves staging surgery or debulking surgery followed by platinum-based combination chemotherapy for early stage disease or advanced diseases, respectively [
4,
5]. Clinical evidence has shown that the standard combined chemotherapy of ovarian cancer is carboplatin-paclitaxel; although two well-designed trials have revealed that no improvement in outcome was associated with a platinum and taxane combination compared with single-agent platinum as initial chemotherapy [
6,
7]. Despite a good initial response to combined chemotherapy, long-term survival remains poor. In our study, all of the patients with EOC underwent primary surgery with an optimal rate of 74.5%. These patients received PC or TP combined chemotherapy according to their economic status. All of the patients completed the planned chemotherapy courses. The five-year PFS rate was 28.3% for all stages and 17.7% for FIGO III–IV stage. The five-year OS rate was 39.2% for all stages and 30.8% for FIGO III–IV stage. Our study obtained a similar five-year survival for all stages (39.2% vs. 44%) compared with patients treated according to the standard protocol of NCCN [
1]. In particular, the five-year OS for FIGO III–IV patients is comparative to data reported in the Cancer Statistic in 2012 (30.8% vs. 27%) [
1]. Our data suggested that optimal primary surgery followed by platinum-based chemotherapy can be performed to ensure the prognosis of patients with advanced EOC.
However, the five-year survival of our patients with FIGO I–II is relatively lower than the previously reported data [
1]. EOC manifests few specific symptoms when tumors are localized in the ovary; thus, patients at the early stage undergo surgery performed by general gynecologists to determine a suspicious benign mass. These patients may be incompletely staged. Previous studies also documented that approximately one-third of the patients at apparent early stage suffer from a more advanced stage when full staging is performed [
5]. In our study, a considerable portion of FIGO I–II patients underwent staging surgery at the Department of General Gynecology in our hospital or even in county hospitals. Therefore, we cannot exclude a few early patients in our group who were not fully staged. Accurate staging should be recognized as a requirement before systemic treatment because subsequent treatment is determined on the basis of the surgical stage of the disease. If EOC cannot be excluded, gynecological oncologists should perform the surgery of patients with adnexal mass. If possible, patients who have had inadequate staging should be referred to an experienced gynecological oncologist for re-staging.
Previous studies showed that clinico-pathological factors (tumor stage, histological grade, and residual tumor) may have prognostic significance. Many authors agree that FIGO stage and residual tumor are two of the most powerful prognostic factors of EOC. In our study, univariate analysis results revealed that advanced FIGO stage, serum CA125, and suboptimal debulking were significant factors of PFS and OS. By comparison, multivariate analysis results showed that FIGO stage and suboptimal debulking were the prognostic factors of poor PFS. However, only advanced FIGO stage was an independent predictor of poor OS. Therefore, the diagnosis of ovarian cancer at an early stage has a greater chance of survival. The development of a highly sensitive and specific test to detect early-stage ovarian cancer has been considered as key to change the “silent killer” to a detectable and highly curable disease. However, at present, no proven test has shown efficient outcomes [
8]. Hence, an urgent need for more sensitive biomarkers is important to detect ovarian cancer at early stages.
Our study is limited by its retrospective design. Two important issues should be addressed when the present results are interpreted. After 2002, the definition that optimal debulking is a residual disease of less than 1 cm was widely accepted [
9]. Nevertheless, surgery that aims to debulk less than 1βcm was progressively performed in our hospital in the first two years of the study period (i.e., from 2002 to 2003). Another issue considers the histological type. The proportion of undifferentiated adenocarcinoma was very high (20.3% or 51/251) in our series. These drawbacks may be attributed to neither residual tumor nor histological type as an independent parameter for prognosis. Therefore, these factors should be further investigated with a larger series of better materials.
In summary, our study confirms the efficacy of debulking surgery followed by a platinum-based chemotherapy for the treatment of EOC. FIGO stage is one of the most reliable predictors of prognosis. Future advances in early diagnosis and novel targeted therapies will probably improve the outcomes of patients with ovarian cancer.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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