1 INTRODUCTION

Ovarian cancer (OC) is considered the seventh most common cancer among women worldwide. The most common type of OC is epithelial ovarian cancer (EOC) which is the most lethal gynecologic malignancy in adult women.1 The estimated overall 5-year survival rate for early-stage epithelial ovarian cancer patients (ESEOC: stages I and II) and patients with advanced-stage epithelial ovarian cancer (ASEOC: stages III and IV) varies between 55% and 92% and 18% and 30%, respectively.2, 3

The statistical measures made at the time of diagnosis are traditionally used for evaluating the survival rate. In this regard, two types of traditionally used survival estimates in previous studies are overall survival (OS) and disease-free survival (DFS) which are reported from the time of diagnosis and remission, respectively.3-6 Despite providing important information for both clinicians and patients, such analyses appear to be of less value for patients who survive a period of time after their initial diagnosis and treatment.7 Although most patients with EOC attain remission, most of them eventually relapse. Follow-up attentions including the close monitoring of CA-125 levels, imaging tests, and physical exams are necessary and important in affecting disease outcomes.8, 9 A more accurate estimate for these patients is conditional DFS (CDFS) which considers changes in the patients' recurrence risks over time.7

Moreover, a recent clinical trial demonstrated that initiating chemotherapy for EOC patients with CA-125 elevation and without symptoms did not offer any more benefits than delaying treatment until the emergence of clinical evidence of disease recurrence.10 Additionally, the early treatment of the relapsed EOC patients based on the rise of CA-125 levels alone has resulted in the earlier deterioration of their quality of life.10 In these situations, using traditional DFS (TDFS) may not provide realistic and optimistic information about the recurrence risk for EOC patients, and CDFS estimates might offer more accurate information regarding the risk of recurrence so that the best-informed decisions about the patients' follow-up care can be made.7

Today, the risk of recurrence from the time of treatment or surgery can be computed using the available instruments for predicting the recurrence risk of EOC. CDFS estimates are based on the definition of conditional survival probability. These estimates incorporate the dynamic change in the survival risk over time. Therefore, they have been recognized as a more meaningful indicator of the survival probability of patients who have an initial survival period.7, 11

The median DFS was reported to be 2.54 years (range: 0.03-9.96 years) among patients with OC in a previous study. Moreover, 3-year DFS was 48.2%.12

The stage and histological type can affect the OS of patients with EOC. Moreover, age ≥ 60 years was correlated with poorer overall survival than age <60 years in a previous study.13 Another study showed that chemotherapeutic regimens/cycles and tumor grade and stage were independent prognostic factors for early-stage EOC. Moreover, no significant differences were observed between 5-year OS and histological types.14

Considering the insufficient data in the literature, this study aimed to determine the conditional disease-free survival (CDFS) rates and their associated determinants in Iranian patients with EOC.

2 METHODS 2.1 Sampling population

This cohort study retrospectively reviewed the clinical and demographic data of women newly diagnosed with EOC at Motahari Clinic (a single tertiary referral hospital, Shiraz, Iran) from 2001 to 2016. The study protocol was approved by the Ethics Committee for Research of Shiraz University of Medical Sciences (Protocol# IR.SUMS.REC.1393.8910) and was conducted in compliance with the Declaration of Helsinki. Patients with nonepithelial ovarian cancer, tumors with an unknown or not applicable stage, borderline histology tumor, undefined histological types, without pathology confirmation, and lost to follow-up were excluded. Besides, the patients who did not provide signed informed consent for the analysis of their medical records and those with nonanalyzable data (deficit in data) were also excluded.

The age at diagnosis, marriage status, child-bearing (parity), tumor histology, and the FIGO (International Federation of Gynecology and Obstetrics) stage were considered for the analysis. The FIGO classification was used for disease staging and histological grading.6 Stages I and II were considered as ESEOC and stages III and IV were regarded as ASEOC. As the first-line chemotherapy regimen, platinum-paclitaxel was given to patients eligible for chemotherapy (except for patients with stage IA and grade I disease). According to the opinion of the physician and the tolerance of patients to the side effects of chemotherapy, three to six cycles of chemotherapy were applied.

2.2 Analysis of the survival time

The primary endpoint was DFS. The time interval between the initial remission date and the recurrence date or the last contact was considered as the DFS time. Patients without diagnosed recurrent EOC during the follow-up period were censored at the end of the study. The date of diagnosis was defined as the date of the primary surgery in patients without cytology or the date of the first positive cytology. The date on which no evidence of disease was found by the oncologist was considered as the date of remission. If this information was missing, the date of the first negative surgical or imaging result or the date of the first factor indicating no evidence of disease such as normal levels of CA-125 was used for defining the date of remission. When none of these criteria were available, 1 month after the date of chemotherapy completion or (if no chemotherapy was given) the date of the primary surgery was used. Recurrence was defined as a return of clinical symptoms on follow-up after the patient has been in remission for a while. The date of recurrence was defined based on a process similar to the one applied for the date of remission. If the date on which an oncologist first diagnosed any signs of recurrence was available, it was considered as the date of recurrence. The date of the first positive surgical or imaging result, the initiation date of chemotherapy/radiation, or the date of the first evidence indicating disease recurrence such as elevated CA-125 levels after being disease-free for a while was used as the recurrence date. The TDFS rates were calculated by nonparametric Kaplan–Meier (NPKM) estimates and compared using the log-rank test.15

The simultaneous impact of various patients' characteristics on the DFS was analyzed using the multiple covariate Cox-adjusted proportional hazards (PH) model and employing the Breslow method for the ties. After assessing the PH assumption (using the goodness-of-fit testing approach based on Schoenfeld residuals), the findings were interpreted using hazard ratios (HRs). The confidence intervals (CIs) for the HRs were computed based on Wald's test of the Cox-adjusted PH regression parameters. The landmark analysis method was applied with six landmark time points (at baseline and after 1, 2, 3, 4, and 5 years from the baseline).

2.3 Conditional disease-free survival (CDFS)

CDFS estimates were directly calculated from traditional NPKM disease-free survival estimates. CDFS is defined as the probability of staying disease-free for an additional number of years (t2) provided that a patient has already been in remission for t1 number of years. It is expressed as CDFS (t2|t1). The exponential version of Greenwood's formula (see Appendix A) was used to compute the CDFS estimates with a confidence interval (CI) of 95%.16 The changes in DFS over time were evaluated by comparing the estimations of 1- and 3-year CDFSs (CDFS (1|x) and CDFS (3|x)) at 1, 2, 3, 4, and 5 years after attaining remission with baseline 1- and 3-year DFS estimates. In addition to the overall CDFS, to assess the impact of EOC women's characteristics, 1- and 3-year CDFS estimates were also calculated within the strata defined by age at diagnosis, marriage status, parity, stage, and histology.

All the statistical analyses were performed using the R software (version: 3.6.2) and GraphPad Prism software (version: 6.07). A p-value of ≤.05 was considered statistically significant.

3 RESULTS

After applying the exclusion criteria to a total of 600 EOC patients who were evaluated, 335 patients were considered for the analysis. The mean ± SD age at diagnosis of the women was 48.2 ± 13.0 years (range: 18-80 years) and 295 patients (88.1%) were married. The majority of the patients had a parity of 2-5 (41.8%), followed by >5 parity (28.6%), nulliparous (20.9%), and 1 parity (8.7%).

The median (95% CI) OS was 3.58 (3.00-4.17) years (ranging from 0.25 to 13.33 years). About 61.2% of the women were diagnosed with recurrent EOC, and 38.8% of them were still alive at the termination of the study. The median (95% CI) DFS for the women was 2.75 (2.25-3.42) years (range: 0.08-13.00 years). One-, 2-, 3-, 4-, 5-, 7-, and 10-year traditional DFS rates (95% CI) for the EOC patients were calculated as 81.1% (76.4-84.9%), 59.6% (53.9-64.8%), 47.0% (41.2-52.7%), 40.2% (34.4-46.0%), 35.5% (29.7-41.3%), 25.6% (19.8-31.8%), and 21.8% (15.6-28.7%), respectively (Figure 1A). The descriptive analyses demonstrated that 32.5%, 5.7%, 47.2%, and 14.6% of the study population had been diagnosed with stages I, II, III, and IV EOC, respectively. 53.0%, 6.7%, 32.9%, and 7.4% of the women who survived 5 years without recurrence had stages I, II, III, and IV EOC, respectively. Moreover, 81.8%, 10.7%, 3.3%, and 4.2% of the patients were diagnosed with serous epithelial, mucinous, and endometrioid carcinomas as well as other types of tumor (i.e., Brenner, undifferentiated carcinoma, and clear cell carcinoma) at baseline, respectively, while the EOC women who survived 5 years without recurrence were 76.5%, 15.4%, 3.4%, and 4.7% in the above-mentioned histological subgroups, respectively.

The nonparametric Kaplan–Meier survival curves of overall disease-free survival (A) according to the categories of age (B), marriage status (C), stage (D), parity (E), and histology (F). The log-rank test statistic and the associated p-value are also shown for the comparison of various survival curves

Using the nonparametric log-rank test analysis, the age of >55 years at diagnosis led to lower TDFS estimates (p = .0001) and women with ESEOC had significantly higher TDFS estimates than those with ASEOC (p < .0001). Moreover, the TDFS curves were not statistically significant in terms of marriage status (p = .1454), different histological subtypes (p = .1107), and child-bearing or parity (0.0901) (Figure 1).

Landmark analyses were applied based on the multiple covariate Cox-adjusted PH regression (Table 1) to establish the impact of various factors on the DFS at baseline and five subsequent years of remission. At baseline, the data analysis of all the 335 eligible patients demonstrated that a higher stage tumor (II: HR [95% CI]: 2.91 [1.40-6.04], p = .004; III: HR [95% CI]: 5.20 [3.39-7.99], p < .001; IV: HR [95% CI]: 6.46 [3.96-10.56], p < .001) and endometrioid histology (HR [95% CI]: 2.59 [1.14-5.89], p = .023) were associated with a higher risk of recurrence when compared to stage I and the other histological subtypes, respectively. For the 1- to 5-year landmark time points, the DFS was evaluated from the specified landmark time point, and only EOC women who were still disease-free at that landmark time point were considered in the analyses. The two previous factors (a higher stage tumor and endometrioid carcinoma) remained significant predictive factors of the DFS during five subsequent years of remission. Moreover, aging was also associated with a higher risk of recurrence at 1- and 3-year landmark time points. This study showed that the hazard of recurrence for older women with the age at diagnosis of ≥55 years was approximately twice and three times more than that of young women aged <45 years at 1- and 3-year landmark time points, respectively (1-year: HR [95% CI]: 1.70 [1.01-2.87], p = .047; 3-year: HR [95%CI]: 3.71 [1.35-10.20], p = .011).

TABLE 1. The hazard ratios (95% CIs) for recurrence using landmark analysis based on the multiple covariate Cox-adjusted regression at baseline and the 1st, 2nd, 3rd, 4th, and 5th years of remission Baseline (N = 335) 1st year of remission (N = 264) Prognostic factor N E HR (95% CI) p N E HR (95% CI) p Age at diagnosis (year) <45 133 68 Reference - 106 41 Reference - 45-55 97 59 1.06 (0.73-1.54) .759 84 46 1.43 (0.91-2.25) .121 >55 105 78 1.45 (0.97-2.18) .072 74 47 1.70 (1.01–2.87) .047* Marriage status Single 40 23 Reference - 30 13 Reference - Married 295 182 1.20 (0.63-2.29) .575 234 121 1.52 (0.66-3.50) .324 Parity 0 70 41 Reference - 53 24 Reference - 1 29 17 0.96 (0.49-1.88) .897 24 12 1.06 (0.46-2.44) .900 2–5 140 80 0.73 (0.43-1.22) .231 114 54 0.68 (0.35-1.33) .262 >5 96 67 0.82 (0.47-1.42) .469 73 44 0.80 (0.39-1.62) .534 Stage I 109 36 Reference - 104 31 Reference - II 19 10 2.91 (1.40–6.04) .004* 16 7 2.66 (1.12-6.31) .026* III 158 115 5.20 (3.39–7.99) <.001* 112 69 4.54 (2.77-7.44) <.001* IV 49 44 6.46 (3.96–10.56) <.001* 32 27 5.67 (3.18-10.13) <.001* Histology Serous 274 174 Reference - 214 114 Reference - Mucinous 36 17 1.00 (0.60-1.68) .993 30 11 0.83 (0.44-1.59) .581 Endometrioid 11 7 2.59 (1.14–5.89) .023* 10 6 3.04 (1.21-7.62) .018* Other typesa 14 7 2.06 (0.95-4.45) .066 10 3 2.05 (0.63-6.64) .232 2nd year of remission (N = 206) 3rd year of remission (N = 174) Prognostic factor N E HR (95% CI) p N E HR (95% CI) p Age at diagnosis (year) <45 91 26 Reference - 78 13 Reference - 45–55 64 26 1.62 (0.89-2.95) .115 54 16 2.48 (1.07-5.73) .033* >55 51 24 1.98 (0.95-4.15) .068 42 15 3.71 (1.35–10.20) .011* Marriage status Single 26 9 Reference - 24 7 Reference - Married 180 67 0.92 (0.24-3.51) .903 150 37 0.66 (0.13-3.36) .618 Parity 0 41 12 Reference - 38 9 Reference - 1 22 10 3.18 (0.84-12.06) .088 14 2 1.09 (0.10-12.35) .946 2–5 90 30 0.97 (0.28-3.29) .959 81 21 0.94 (0.21-4.24) .933 >5 53 24 1.28 (0.35-4.72) .711 41 12 0.97 (0.18-5.08) .971 Stage I 98 25 Reference - 92 19 Reference - II 14 5 3.84 (1.31-11.24) .014* 12 3 4.00 (0.93-17.26) .062 III 73 30 3.70 (1.96-7.01) <.001* 56 13 2.46 (1.01-6.00) .047* IV 21 16 6.40 (3.07-13.33) <.001* 14 9 5.95 (2.34-15.13) <.001* Histology Serous 161 61 Reference - 133 33 Reference - Mucinous 27 8 0.86 (0.39-1.91) .712 24 5 0.64 (0.22-1.84) .403 Endometrioid 9 5 5.00 (1.69-14.78) .004* 9 5 7.65 (2.31-25.32) .001* Other typesa 9 2 4.20 (0.92-19.16) .064 8 1 38.68 (1.92-777.6) .017* 4th year of remission (N = 158) 5th year of remission (N = 149) Prognostic factor N E HR (95% CI) p N E HR (95% CI) p Age at diagnosis (year) < 45 76 11 Reference - 74 9 Reference - 45–55 46 8 1.58 (0.56-4.41) .386 43 5 1.06 (0.25-4.51) .933 >55 36 9 2.18 (0.63-7.56) .220 32 5 1.27 (0.23-7.10) .785 Marriage status Single 21 4 Reference - 20 3 Reference - Married 137 24 1.00 (0.17-5.96) .996 129 16 1.12 (0.14-8.86) .917 Parity 0 35 6 Reference - 34 5 Reference - 1 12 0 NA NA 12 0 NA NA 2–5 75 15 0.81 (0.17-3.82) .788 71 11 0.67 (0.12-3.74) .648 >5 36 7 0.67 (0.10-4.37) .677 32 3 0.20 (0.01-3.21) .257 Stage I 84 11 Reference - 79 6 Reference - II 11 2 7.41 (1.14-48.36) .036* 10 1 33.20 (2.14-515.95) .012* III 51 8 2.93 (0.92-9.39)