Tumor stage is the strongest prognostic variable for epithelial ovarian cancer. As far as early disease is concerned, the International Federation of Gynecology and Obstetrics (FIGO) Annual report n 26 showed that 5-year overall survival was 89.6% for stage IA, 86.1% for stage IB, 83.4% for stage IC, and 70.7% for stage IIA.1 Bilateral salpingo-oophorectomy with total abdominal hysterectomy and comprehensive surgical staging is the keystone of treatment for patients with early-stage epithelial ovarian cancer.2–7 Fertility-sparing surgery, associated with complete surgical staging, seems to achieve equivalent clinical outcomes in highly selected cases of young women wishing to preserve childbearing potential.8 The role of adjuvant chemotherapy has been long debated.2,9–13 The meta-analysis of 5 randomized controlled trials showed that women who received adjuvant platinum-based chemotherapy had better progression-free survival (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.53–0.84) and better overall survival (HR, 0.71; 95% CI, 0.53–0.93) than those who did not.13 Subgroup analysis suggested that the benefit from adjuvant chemotherapy is mainly restricted to patients with nonoptimal surgical staging.14 There is no general agreement for the optimal chemotherapy for early epithelial ovarian cancer. Most authors use the combination of paclitaxel plus carboplatin, which is the standard regimen for advanced disease, although this extrapolation cannot be completely justified, and single-agent carboplatin can represent a rational therapeutic option.3,15–18 Higher substage, higher tumor grade, clear cell histology, tumor rupture, and positive peritoneal washing are associated with a higher risk of failure.9,10,15,16,18–22 Very few articles have specifically assessed the clinical outcome of patients with early-stage epithelial ovarian cancer who will ultimately develop recurrent disease following surgery with23 or without adjuvant therapy.24
The aim of this multicenter retrospective Italian study was to analyze the survival after recurrence and the clinical outcome of patients with recurrent early-stage epithelial ovarian cancer.
MATERIAL AND METHODS
Between January 1985 and December 2009, 467 patients underwent primary surgery followed by either adjuvant chemotherapy or observation alone for early-stage epithelial ovarian cancer at the Departments of Gynecology and Obstetrics of the University of Pisa, Brescia, and Turin. Patients referred following surgery performed in other hospitals were not taken into consideration. This retrospective study was conducted on the 87 (18.6%) of the 467 patients who subsequently developed clinically and/or radiologically detectable recurrent disease.
The hospital records, included surgical notes and pathological reports. Of these, 87 were collected using a common form with standardized items and a common database.
An asymptomatic patient with rising CA-125 levels and negative clinical and imaging examinations was not considered to have recurrent disease and underwent a more stringent follow-up program.
Patient characteristics at initial diagnosis (date, age, type of surgery, FIGO stage, histological type, tumor grade, adjuvant chemotherapy) and at the time of relapse (date, site of recurrence, number of recurrence sites, serum CA-125 at recurrence, examination that first detected recurrence, and treatment at recurrence) were reported for each case.
At presentation, tumor stage and histological diagnosis were determined according to FIGO criteria and the histological typing system of the World Health Organization, respectively. Tumors were graded as well (G1), moderately (G2), or poorly (G3) differentiated. The histological material was reviewed by the same pathologists in each center.
The time interval from primary surgery to the clinical and/or radiological detection of recurrence was defined as time to recurrence.
Tailored treatment at recurrence was established on the basis of the site and type of relapse, time to recurrence, prior adjuvant therapy, and patient characteristics. Surgery was usually taken into consideration for women with good physical condition, time to recurrence longer than 6 months, no clinical evidence of ascites, no extra-abdominal metastases (except groin or abdominal wall), and relapse sites retained to be potentially resectable according to imaging studies.
The evaluation of the course of the disease after recurrence was based on clinical examination, serum CA-125 assay, chest x-rays, abdominal-pelvic ultrasound, and/or computed tomography (CT) scan. Further investigations were performed where appropriate.
The patients were followed up until they died or until May 2012. The median follow-up of survivors from the detection of recurrence was 87.6 months (range, 6.1–189.9 months).
The SAS statistical package (release 8.2; SAS Institute, Cary, NC) was used for computations. The time from detection of the first recurrence to death or last observation was defined as survival after recurrence. The time from primary surgery to death or last observation was defined as overall survival. The analyzed prognostic variables included patient age, FIGO stage, histological type, tumor grade, prior adjuvant chemotherapy, time to recurrence, site of recurrence, examination that first detected recurrence, and treatment at recurrence (surgery and type of chemotherapy).
Survival analyses were performed according to the Kaplan-Meier product-limit method. Differences between groups were evaluated by the log-rank test. A multiple regression analysis based on the Cox proportional hazards model was used to jointly test the relative importance of variables as predictors of survival times.
Patient characteristics at initial diagnosis are summarized in Table 1. Seven patients (8.4%) underwent conservative surgery. An adequate surgical peritoneal staging and an adequate surgical peritoneal plus retroperitoneal staging were performed in 39 (44.8%) and 41 (47.1%) cases, respectively. As far as the 10 women with stage IIA disease are concerned, 6 had undergone a peritoneal staging, and 4 had undergone a peritoneal plus retroperitoneal staging.
Of the 31 women with early-stage serous histological subtype, 3 patients had grade 1 tumor, 12 had grade 2 tumor, and 16 had grade 3 tumor. As far as the 10 women with stage II disease are concerned, 3 patients had grade 2 serous tumor, 2 had grade 3 serous tumor, 2 had grade 3 endometrioid tumor , 1 patient had grade 1 endometrioid tumor, 1 had a clear cell tumor, and 1 had an undifferentiated tumor.
After initial surgery, 68 patients (78.2%) received adjuvant chemotherapy, which was platinum-based in 51 cases (75.0%) and paclitaxel- and platinum-based in 15 cases (22.1%).
Patient characteristics at relapse are shown in Table 2. The 25%, 50%, and 75% quantiles of time to recurrence were 15, 25, and 44 months, respectively. The pelvis was the most common site of recurrent disease (39.1% of the cases), followed by abdomen (18.4%) and retroperitoneal nodes (18.4%). At the time of recurrence, serum CA-125 was raised in 35 (63.6%) of the 55 patients in whom this marker was assayed. Computed tomography scan was the examination that first detected the recurrent disease in 44 cases (50.6%). All the relapses first detected by gynecologic and physical examination or ultrasound were then confirmed radiologically.
Treatment at recurrence consisted of chemotherapy in 46 patients, surgery plus chemotherapy in 29, surgery in 3, surgery plus radiotherapy in 2, and other therapies in 7 patients.
Table 3 reports the sites and times of relapse and the clinical outcome of the 34 women who underwent surgery for recurrence. Pelvis was the most common site of failure (n = 17) followed by retroperitoneal or groin lymph nodes (n = 7); time to recurrence was 6 to 12 months in 6 patients, 13 to 24 months in 9, and more than 24 months in 19; and additional treatment consisted of chemotherapy in 29 cases (platinum/paclitaxel-based chemotherapy in 19, platinum-based chemotherapy in 6, and single-agent paclitaxel in 4). A macroscopically complete surgical cytoreduction was obtained in 29 (85.2%) of the 34 patients.
At the time of the present analysis, 57 of the 87 patients included in the study died of tumor after a median time of 17 months from recurrence (range, 3–123 months), 4 patients died of intercurrent disease with no clinical evidence of tumor (after 30, 51, 81, and 130 months, respectively), 3 patients are still alive with clinical evidence of tumor (after 12, 32, and 190 months, respectively), and 23 patients are still alive with no clinical evidence of tumor after a median of time of 90 months (range, 6–174 months).
In the whole series, 5- and 7-year survival rates after recurrence were 34.3% and 29.6%, and 5- and 7-year overall survival rates were 59.0%, and 36.6%.
By log-rank test, survival after recurrence was significantly related to patient age (≤60 vs >60 years; P = 0.001), time to recurrence (>15 vs ≤15 months; P = 0.049), site of recurrence (retroperitoneum vs pelvis vs other; P = 0.004), and surgical treatment at recurrence (yes vs not; P = 0.001), but not to FIGO stage, histological type, tumor grade, prior adjuvant chemotherapy (yes vs not), examination that first detected recurrence, and chemotherapy at recurrence (Table 4).
On multivariate analysis, patient age (χ2 = 4.702; HR, 1.836; 95% CI, 1.060-3.180; P = 0.03) and surgical treatment at recurrence (χ2 = 4.946; HR, 1.972; 95% CI, 1.084–3.587; P = 0.026) were independent prognostic variables for survival after recurrence.
By log-rank test, overall survival was significantly related to patient age (≤60 vs > 60 years; P = 0.002), time to recurrence (≤15 vs >15 months; P = 0.0001; ≤25 vs >25 months; P = 0.001; ≤44 vs >44 months; P = 0.008), site of recurrence (retroperitoneum vs pelvis vs other; P = 0.02), surgical treatment at recurrence (yes vs not; P = 0.002), and chemotherapy regimen at recurrence (platinum/paclitaxel-based chemotherapy vs platinum-based chemotherapy vs non–platinum-based chemotherapy; P = 0.027), but not to FIGO stage, histological type, tumor grade, prior adjuvant chemotherapy, and examination that first detected recurrence (Table 5).
On multivariate analysis, patient age (χ2 = 4.131; HR, 1.872; 95% CI, 1.023-3.428; P = 0.042), surgical treatment at recurrence (χ2 = 3.950; HR, 2.052; 95% CI, 1.010–4.169; P = 0.047), and time to recurrence (>15 vs ≤15 months, χ2 = 11.183; HR, 0.300; 95% CI, 0.148-0.608; P = 0.001) were independent prognostic variables for overall survival.
Five-year disease-free survival for patients with early-stage epithelial ovarian cancer ranges from 61% to 86%.2,10–12,17,18,21 Platinum-based chemotherapy is effective in improving the clinical outcome, although the patients submitted to optimal surgical staging seem to have little gain from this adjuvant treatment.13,14 The optimal number of adjuvant chemotherapy cycles is still matter of debate.15,16 Platinum- and paclitaxel-based chemotherapy is able to achieve a clinical complete response and a pathological complete response in about 50% and 25%, respectively, of patients with advanced epithelial ovarian cancer.25,26 However, more than 50% of complete responders will ultimately relapse, and patients with recurrent disease will experience a very poor prognosis, with a 5-year survival from recurrence lower than 10%.
Early stages account for approximately 25% of the cases of epithelial ovarian cancer, and their risk of relapse ranges from 13% to 31%.2,9,15,19,21–24 Most recurrences involve the pelvis or abdomen, and median time to recurrence ranges between 11 and 29 months.2,9,10,19 Our data about rates, sites, and times of relapse are consistent with the literature. Limited data are available on the outcomes of patients with recurrent early-stage epithelial ovarian cancer.23,24 A retrospective study on 194 patients who underwent surgery followed by observation reported that 61 (31%) of them experienced a relapse after a median time of 17 months.24 Platinum-based chemotherapy was given to 55 of these patients, and 5-year progression-free survival from salvage chemotherapy was 24%. Clear cell histology and preoperative cyst rupture were independent prognostic factors for progression-free survival in those women who experienced relapse, whereas tumor grade was not related to the clinical outcome of these patients. The prognosis of the 61 patients with early-stage disease who had a relapse following observation was similar to that of the 261 patients who had stage III disease at presentation and who received platinum-based chemotherapy within 2 prospective randomized trials.27,28 In particular, the survival curve of patients with recurrent early-stage disease in the first 2 years after relapse mimicked that of patients with suboptimally debulked stage III disease, whereas the survival curve after 4 years from relapse was similar to that of patients with optimally debulked stage III tumor.24 Chan et al23 assessed the 74 women with early-stage disease enrolled in the Gynecologic Oncology Group (GOG) 157 trial, who developed recurrent disease following adjuvant chemotherapy with paclitaxel plus carboplatin. Median time from completion of chemotherapy to recurrence was 21 months, and median survival after recurrence was 24 months in the entire series, 35 months in the patients with treatment-free interval greater than 24 months, and 10 months in those with treatment-free interval less than 24 months (P = 0.003). Conversely, the type of salvage chemotherapy had no prognostic relevance. Median survival of these patients with recurrent early-stage disease was not significantly different from that of the patients with recurrent, optimally debulked stage III disease enrolled in the GOG 158 trial25 and from patients with recurrent, suboptimally debulked stage III-IV disease enrolled in the GOG 152 trial (24 vs 21 vs 20 months, respectively).29
In our series, 5- and 7-year survival rates after recurrence were 34.3% and 29.6%, and patient age and surgical treatment at recurrence were independent prognostic variables. The patients who underwent surgery at recurrence had a significantly better clinical outcome than those who did not. The majority of the former had a pelvic or lymph node recurrence. Conversely, the study of Chan et al,23 who examined patients with recurrent early-stage epithelial ovarian cancer following adjuvant chemotherapy, lacked information on site of failure and secondary cytoreductive surgery. A consensus regarding the role of salvage surgery in recurrent epithelial ovarian cancer has not yet been reached, although several retrospective studies seem to suggest a survival benefit for patients with optimal secondary cytoreduction.30–32 In our series, secondary surgery was usually taken into consideration for women with good physical condition, long time to recurrence, no clinical evidence of ascites, no extra-abdominal metastases, and relapse sites retained to be potentially resectable according to imaging studies. A macroscopically complete cytoreduction was obtained in 85.2% of the women who underwent secondary surgery. These data are in agreement with the results of the Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer (DESKTOP OVAR) trial, which reported a complete resection in 79% of the patients with recurrent epithelial ovarian cancer who had FIGO stage I-II or FIGO stage III-IV with no residual tumor after first surgery, performance status of 0, and absence of ascites.33 To our knowledge, no article has specifically investigated the role of surgery in patients with recurrent early-stage epithelial ovarian cancer. The present data appear to suggest that, when feasible, salvage surgery gives a survival advantage in this clinical setting.
In conclusion, although patients with early-stage epithelial ovarian cancer have a good survival, the clinical outcome of those who develop recurrent disease is poor. The clinical and pathological features with prognostic relevance at presentation (ie, tumor substage, histological type, tumor grade) seem to be less important for the prediction of survival of women with recurrent early-stage disease. The patients who undergo secondary surgery seem to have the most favorable outcome. However, the retrospective study design, the long time span for case collection, the inclusion of both patients who received adjuvant chemotherapy and those who did not, and the lack of standardization of treatment modality at recurrence do not allow to draw definitive conclusions.
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