Endometrial cancer is the 6th most frequent cancer in women worldwide, and it is the 12th most frequent cancer overall.1 Approximately 290,000 new cases were detected in 2008, and it was responsible for nearly 5% of all new cases of cancer in women.
Patients with endometrial cancer are usually diagnosed at early stages; therefore, these patients had an excellent prognosis, and they could be treated with only surgery. In contrast, more than 20% of the patients had extrauterine disease at diagnosis.2 Moreover, 7% to 12% of the patients had metastatic pelvic and/or paraaortic (PA) lymph nodes without spread outside the pelvis.3–6
Endometrial cancer has been surgically staged according to International Federation of Gynecology and Obstetrics (FIGO) since 1988.7 Accordingly, stage IIIC disease was defined as the involvement of lymph nodes without spread to the upper abdomen or outside the abdomen. In 2009, FIGO revised the staging system and divided stage IIIC disease into 2 with regard to the involvement of PA lymph nodes.8 Stage IIIC1 disease was defined as the involvement of only pelvic lymph nodes, and stage IIIC2 disease was defined as the involvement of PA lymph nodes.
The data regarding stage IIIC endometrial cancer is not clear because patients with stage IIIC disease are a heterogeneous group. This makes the prediction of recurrence and survival as well as standardization of the treatment difficult. Patients with stage IIIC endometrial cancer were reported to have 44% to 82% 5-year overall survival (OS) and 33% to 81% progression-free survival (PFS).3–5,9–12 In these studies, age, cell type, FIGO grade, depth of myometrial invasion, nonnodal extrauterine disease, lymphovascular space invasion, distribution of metastatic lymph nodes (stage IIIC1 vs stage IIIC2), number of removed lymph nodes, number of removed metastatic lymph nodes, and adjuvant therapy were shown to be related to recurrence and survival.
Failure in stage IIIC disease is usually in the upper abdomen or outside the abdomen, and it is outside the pelvis in more than 75% of the patients.3,4,10,11 This shows that actually, stage IIIC endometrial cancer is a systemic disease and that we should consider systemic therapy for these patients.
Reported survival rates for stage IIIC disease had a wide range. It is possible for these patients to have 5-year survival greater than 80%, depending on the clinicopathological characteristics of the patients and applied therapies. The outcomes of the patients with stage IIIC disease will be improved by a detection of the factors associated with survival. Therefore, in this study, we aimed to evaluate the recurrence pattern and survival in patients with stage IIIC1 to IIIC2 endometrial cancer and to define the demographic, surgicopathological, and treatment-related factors associated with recurrence and survival in these patients.
MATERIALS AND METHODS
A total of 147 patients who underwent staging surgery and had a diagnosis of stage IIIC1 to IIIC2 endometrial cancer according to the FIGO 2009 between January 1993 and May 2013 were included. Surgicopathological data were obtained from the gynecologic oncology department’s electronic database. Patients with uterine sarcoma or sarcomatous component, patients whose data and medical reports could not be obtained, and patients with synchronous tumors were excluded. Serous, clear cell, and undifferentiated tumors were defined as FIGO grade 3 tumor. Adnexal involvement, spread to the uterine serosa, and positive peritoneal cytology were accepted as nonnodal extrauterine disease. Period from surgery to recurrence or last visit was defined as PFS, and period from surgery to death because of the disease (except in the first month after surgery) or last visit was defined as disease-specific survival (DSS). We defined recurrence distal to the pelvic inlet (true pelvis) as pelvic recurrence, recurrence between pelvic inlet and diaphragm as upper abdominal recurrence, and all the rest of recurrences as extra-abdominal recurrence. Although ascites and peritonitis carcinomatosa were accepted as upper abdominal recurrence, recurrence in the liver parenchyma, skin, and bone were accepted as extra-abdominal recurrence.
Frozen/section is used routinely in patients with endometrial cancer in our clinic, and staging surgery is performed for the patients whose frozen/section revealed nonendometrioid adenocancer, FIGO grade 2 or 3 disease, depth of myometrial invasion being ½ or greater, cervical involvement, and a tumor size greater than 2 cm. Furthermore, patients with a preoperative diagnosis of FIGO grade 3 disease or cell type with high risk undergo staging surgery directly. Staging surgery standardly involves total abdominal hysterectomy + bilateral salpingo-oophorectomy + systematic pelvic and PA lymphadenectomy + omentectomy + cytologic sampling. In case of intraoperative identification of macroscopic disease, cytoreductive surgical techniques are used in addition to staging surgery.
Lymphadenectomy was performed in most of the patients by skeletonizing pelvic and PA regions. Nevertheless, there were patients treated by sampling of the suspicious lymph nodes at the discretion of the surgeon. Because patients with positive lymph nodes were evaluated, patients who had lymph node sampling were also included in the study.
Bilateral pelvic lymphadenectomy was performed to complete skeletonization, with all lymphatic tissue of the common, external, and internal iliac vessels and the obturator fossa that was removed after visualization of the obturator nerve. The superior surgical dissection margin for the pelvic nodes was the aortic bifurcation, and the anterior distal surgical dissection margin was the circumflex iliac vein. The presacral lymphatic tissue was harvested separately. Each of common iliac, external iliac, internal iliac, obturator, and presacral regions were accepted as part of the pelvic region. The upper limit of PA lymphadenectomy was renal veins. All lymphatic tissue was then harvested from the precaval, paracaval, interaortacaval, preaortic, and PA regions up to the renal veins. The lymph node–bearing tissue from the pelvic lymph region and the PA region was submitted for analysis. All surgeries and pathologic findings were performed and interpreted at a single institution.
In terms of adjuvant therapy, only radiotherapy or concomitant radiochemotherapy (with cisplatin) or sandwich therapy (3 cycles of paclitaxel + carboplatin followed by radiotherapy followed by 3 cycles of paclitaxel + carboplatin) or only chemotherapy or chemotherapy followed by radiotherapy or hormonal therapy were applied at the discretion of the surgeon. Radiotherapy was given to the pelvic region in case of only pelvic nodal involvement, whereas it was given as extended-field radiotherapy in patients with PA lymph node metastasis or without sufficient evaluation of the PA lymph nodes.
Patients were followed up every 3 months for 2 years after adjuvant therapy, every 6 months until the fifth year after treatment, and yearly thereafter. In every follow-up, pelvic examination, abdominal ultrasonography, complete blood count, and blood chemistry were performed. Chest x-ray was used yearly or in case of clinical suspicion. Thoracic and/or abdominal computerized tomography was used when needed. Ca-125 level and Papanicolaou test were used in the follow-up, although they were not used routinely.
Prognostic demographic and histopathological factors were evaluated to determine 3-year PFS and 3-year DSS. The effects of each clinicopathological factor on the recurrence rates and survival in the first 3 years were examined by using the χ2 test. Statistical power of factors was defined by using binary logistic regression analysis. For this reason, factors having a P < 0.05 in univariate analysis were included in the analysis. Survival was calculated with Kaplan-Meier survival analysis. Statistical analyses were performed using SPSS version 17.0 (SPSS Inc, Chicago, Ill). The cutoff for statistical significance was set at P < 0.05.
A total of 1640 patients with epithelial endometrial cancer were operated on between January 1993 and May 2013 in our clinic. Among these patients, 161 (9.8%) had a diagnosis of stage IIIC1 to IIIC2 endometrial cancer according to FIGO 2009. Of these patients, 14 patients, 6 of whom had synchronous tumors and 8 of whom did not have enough data, were excluded. The remaining 147 patients were included.
The mean age of the patients was 58.6 years, ranging between 30 and 81 years. Stage IIIC1 and IIIC2 disease were detected in 63 (42.9%) and 84 (57.1%) patients, respectively. Tumor type was endometrioid for 98 patients, and 62 patients had FIGO grade 3 tumor. Two patients did not have myometrial invasion, whereas 114 patients had ½ or greater myometrial invasion. Peritoneal cytology result was positive in 17 patients. Adnexal involvement and uterine serosal spread were detected in 21 and 8 patients, respectively. Eighty patients had lymphovascular space invasion, and 59 had cervical invasion. Surgicopathological data are shown in detail in Table 1.
Although pelvic and PA lymphadenectomy was performed in 134 patients, 6 patients did not have PA, and 7 patients did not have pelvic lymphadenectomy. Median number of removed lymph nodes was 51.2 (range, 4–119). Median number of PA and pelvic lymph nodes removed were 16.5 (range, 2–41) and 38 (range, 1–78), respectively. The number of removed PA lymph nodes was less than 10 in 34% of the patients. The number of removed pelvic lymph nodes was less than 10 in 7%, less than 15 in 9% and less than 30 in 28% of the patients.
Although 22 (15.6%, n = 141 patients) and 63 (45%, n = 140 patients) patients had isolated PA and isolated pelvic lymph node metastases, respectively, 62 patients (46.3%, n = 134 patients) had both pelvic and PA metastases. Median numbers of PA and pelvic lymph nodes involved were 2 (range, 1–32) and 2 (range, 1–38), respectively.
Because 9 patients were lost to follow-up, 2 patients died of a reason other than cancer (cardiac failure) during chemotherapy, and 1 patient died of a reason other than cancer (pulmonary thromboembolism) in the early postoperative period, 135 patients were included in the survival analysis.
Among the patients in the survival analysis, 128 patients (94.8%) had adjuvant therapy. Sixty-two patients had only radiotherapy, 26 patients had only chemotherapy, 14 patients had sandwich therapy, 18 patients had concomitant chemoradiotherapy, 7 patients had radiotherapy after chemotherapy, and 1 patient had hormonal therapy (megestrol acetate) as adjuvant therapy. Chemotherapy was applied as platin-based combinations (carboplatin + paclitaxel, n = 27; cisplatin + doxorubicin, n = 4; cisplatin + paclitaxel, n = 1; carboplatin, n = 1), and 19 (57.6%) of these patients had 6 cycles of chemotherapy. Seven patients who refused to take adjuvant therapy continued to come to control visits.
Median follow-up time of 135 patients in the survival analysis was 29 months, ranging between 2 and 240 months. Among these patients, 33 patients (24.4%) had recurrence. Three-year PFS and 3-year DSS calculated by Kaplan-Meier survival analysis were 65% and 84%, respectively. The mean time from surgery to recurrence in patients with recurrence was 20 months, ranging between 1 and 56 months. Recurrence was outside the pelvis in 23 patients (70%), and it was extra-abdominal in 20 patients (61%). In contrast, 10 patients had recurrence only in the pelvis. There was recurrence in more than 1 site in 23 patients. Recurrence sites and recurrence times in accordance with the recurrence sites were demonstrated in Table 2.
In the univariate analysis, site of the metastatic lymph nodes and number of removed PA metastatic lymph nodes were associated with 3-year PFS (P = 0.034 and P = 0.034, respectively), and lymphovascular space invasion, site of metastatic lymph node, and presence of recurrence were associated with 3-year DSS (P = 0.036, P = 0.043, and P < 0.001, respectively) (Table 3). When presence of only PA metastasis is compared with presence of only pelvic metastasis and presence of both pelvic and PA metastases, 3-year PFS and 3-year DSS were found to decrease significantly (30%, 73%, and 65%; P = 0.034, 56%, 88%, and 89%; P = 0.043). Three-year PFS improved significantly in case of increased number of removed metastatic PA lymph nodes (lymph node number, ≤2 vs >2; median value) (40% and 70%, respectively; P = 0.034). This factor had a tendency to be effective on 3-year DSS (71% and 94%, respectively; P = 0.085). The relation between the number of removed metastatic PA lymph nodes and 3-year PFS was evaluated in a subgroup analysis including patients with 10 or more metastatic PA lymph nodes. In these patients, 3-year PFS was 43% for the patients with 2 or less metastatic lymph nodes, and it was 60% for the patients with more than 2 metastatic lymph nodes, but this was not statistically significant (P = 0.486). Lymphovascular space invasion was associated with 3-year DSS. Three-year DSS was 100% for the patients without lymphovascular space invasion, whereas it was 73% for the ones having it (P = 0.036). Presence of recurrence was also associated with 3-year DSS. Of the patients with and without recurrence, 52% and 98%, respectively, survived at the end of 3 years (P < 0.001).
The type of adjuvant therapy was not associated with 3-year PFS and DSS in the univariate analysis (Table 3). In the subgroup analysis, there was no statistically significant difference between the groups taking radiotherapy versus chemotherapy (P = 0.454 and P = 0.083, respectively), radiotherapy versus concomitant chemotherapy (P = 0.523 and P = 0.236, respectively), radiotherapy versus sandwich therapy (P = 0.713 and P = 0.747, respectively), chemotherapy versus sandwich therapy (P = 0.421 and P = 0.163, respectively), and sandwich therapy versus concomitant chemoradiotherapy (P = 0.926 and P = 0.554, respectively) in terms of 3-year PFS and 3-year DSS.
There was no association between the type of adjuvant therapy and site of recurrence. The site of recurrence, whether outside the pelvis, was not related to the applied therapy (P = 0.497). Pelvic failure developed in 6 (37.5%) of 16 patients having recurrence after radiotherapy and in 4 (40%) of 10 patients taking chemotherapy. Upper abdominal and extra-abdominal recurrence developed in 12 (75%) and 6 (60%) patients, respectively. Of 2 patients having recurrence after sandwich therapy, one had recurrence in the pelvis, and the other patient had recurrence in the extra-abdominal region. Among the patients having concomitant radiotherapy, 4 patients had recurrence. Of these 4 patients, only 1 patient had recurrence in the pelvis, whereas the others had recurrence in the upper abdomen and extra-abdominal region. In the group of patients who did not take adjuvant therapy, only 1 patient had both upper abdominal and extra-abdominal recurrences (Table 4).
In the multivariate analysis, one model was made with the distribution of metastatic lymph nodes (only PA vs only pelvic and PA + pelvic) and the number of removed metastatic lymph nodes for 3-year PFS, whereas another model was made for 3-year DSS with the distribution of metastatic lymph nodes (only PA vs only pelvic and PA + pelvic), lymphovascular space invasion (negative vs positive), and the presence of recurrence (negative vs positive). Both models were shown to have a high accuracy of estimation in logistic regression analysis. Nevertheless, selected parameters could not be shown to have a statistically significant effect on 3-year PFS as independent factors (Table 5). In contrast, the presence of recurrence was an independent prognostic factor for 3-year DSS. When the presence of recurrence was adjusted for the distribution of metastatic lymph nodes and lymphovascular space invasion, hazard ratio for 3-year DSS was 0.017 (95% confidence interval, 0.002–0.183). Three-year DSS curve is demonstrated in Figure 1.
There is limited number of patient with stage IIIC disease in endometrial cancer, constituting 7% to 12% of the cases.3–6 In this study, at the end of a 20-year experience, approximately 10% of the cases were shown to have stage IIIC disease. In addition, this disease includes a heterogeneous group of patients according to the clinicopathological data, surgical factors, and adjuvant therapies performed. Therefore, demonstrated recurrence and survival rates are variable. Reported 5-year PFS and 5-year OS range between 33% and 81% and 44% and 82%, respectively.3–5,9–12 In this study, 3-year PFS and 3-year DSS were 65% and 84%, respectively. These results were similar to the ones shown in the study by McMeekin et al.4 That study reported 77% for 3-year OS and 65% for 5-year OS.
Age, cell type, FIGO grade, depth of myometrial invasion, distribution of metastatic lymph nodes, the presence of nonnodal extrauterine disease, lymphovascular space invasion, the number of removed lymph nodes, the number of removed metastatic lymph nodes, and adjuvant therapy were shown to be associated with recurrence and survival.3–5,9–12 In our study, the site of metastatic lymph nodes and the number of removed metastatic PA lymph nodes were associated with 3-year PFS, and lymphovascular space invasion, the site of metastatic lymph nodes, and the presence of recurrence were determining factors for 3-year DSS in the univariate analysis. In the multivariate analysis, although any significant clinicopathological factor was not detected for 3-year PFS, not surprisingly, only the presence of recurrence was an independent prognostic factor for 3-year DSS.
Paraaortic nodal involvement is accepted to be a poor prognostic factor for survival.3,9 Paraaortic lymphadenectomy in patients with intermediate- to high-risk disease (depth of myometrial invasion ≥ ½, FIGO grade 3 disease, cervical invasion, and extrauterine spread) is known to improve survival.12–15 However, the site of lymphatic involvement was reported to be unrelated to survival in stage IIIC endometrial cancer.16,17 In this study, 3-year DSS for stage IIIC1 and IIIC2 disease were similar (88% vs 80%, respectively). Nevertheless, the difference between these 2 groups had a tendency to be significant for 3-year PFS (P = 0.094) in our study. Three-year PFS decreased 17% in case of PA nodal involvement. When the relation between the site of lymphatic involvement and survival was analyzed in detail, isolated PA involvement was found to be associated with PFS and DSS in univariate analysis. Interestingly, patients with isolated PA metastasis were shown to have a worse prognosis not only compared with patients with isolated pelvic metastasis but also compared with the patients having both PA and pelvic metastases. Three-year PFS was 30%, 73% and 65%, respectively, and 3-year DSS was 56%, 88% and 89%, respectively. Although this prognostic effect could not be shown in multivariate analysis, explanation of the worse prognostic effect of isolated PA involvement is considered to be related to the spread of the disease. A direct route beginning from the corpus to the PA node–bearing basins by the lymphatic channels adjacent to the gonadal vessels within the infundibulopelvic ligament may exist.18 Mariani et al19 found that, in the absence of Paraaortic lymph node (PALN) metastasis, no metastatic disease was detected in the gonadal veins or surrounding soft tissues. Therefore, we could consider that PA involvement may occur early, depending on the location of the tumor in the corpus.
In this study, interestingly, the relation between removed metastatic lymph node number and survival was different from the literature. In the literature, it is generally shown that the likelihood of recurrence increases and survival decreases as removed metastatic lymph node number increases.9,11,20 However, in the presented study, 3-year PFS was found to be improved as the number of removed PA metastatic lymph nodes increased in the univariate analysis. Nevertheless, this improvement was shown to decrease in patients with higher numbers of removed PA lymph nodes. This situation was considered to be related to the number of removed lymph nodes. It is clear that the likelihood of residual PA nodal disease is high when inadequate PA lymphadenectomy is performed. It means that the number of metastatic lymph nodes will lose significance in case of performance of sufficient lymphatic-tumoral debulking. In the other reported studies, lymphadenectomy was performed in the form of sampling, resulting in a quite low numbers of removed lymph nodes, and the numbers were reported to be lower than 10 for PA lymph nodes and lower than 15 for pelvic lymph nodes. Therefore, in these studies, there is a probability that metastatic lymph nodes may be left behind. In the present study, 3-year PFS was shown to increase by 6% when the number of removed pelvic metastatic lymph nodes increased. Nevertheless, this relation was not significant statistically. The reason of the absence of correlation between 3-year PFS and the number of removed pelvic metastatic lymph nodes was considered to be the performance of pelvic lymphatic-tumoral debulking better than that was performed in PA region. The number of removed PA lymph nodes was lower than 10 in 34% of the patients, whereas for the pelvic lymph nodes, it was lower than 10, 15, and 30 in 7%, 9% and 28% of the patients, respectively.
Lymphadenectomy is performed to provide tumoral debulking and to detect the stage of the disease and to apply the appropriate therapy. The number of removed lymph nodes was reported to be related to survival. In the study of Chan et al21 in which 12,333 patients of the SEER data were evaluated, they showed that there was a correlation between the number of removed lymph nodes and survival in the patients with high-risk endometrial cancer (1988 FIGO stage IB and grade 3, stage IC–IV and all grades). Surprisingly, this association was independent of the number of metastatic lymph nodes. Survival was reported to improve as removed nonmetastatic lymph node number increased. This could be explained by the presence of undefined metastatic lymph nodes. Routine hematoxylin-eosin has a limited efficiency in the determination of the metastatic lymph nodes. In the study of Yabushita et al,22 they showed occult metastasis by using cytokeratin in immunohistochemical evaluation of 20 (30%) of 66 lymph nodes that were reported to be tumor negative with routine dyes in patients with stage IIIC endometrial cancer.
Because stage IIIC endometrial cancer is composed of a heterogeneous group of patients and we have limited information about this stage disease, the applied adjuvant therapy could not be standardized. However, stage IIIC disease could be considered as a systemic disease because most of the recurrences are extrapelvic and because we often see nonnodal extrauterine disease. For this reason, some recommended strongly that systemic adjuvant therapy should be applied to these patients.3,4 In the study of the Gynecologic Oncology Group where they compared whole abdominal radiotherapy and cisplatin + doxorubicin combination chemotherapy in patients with advanced-stage (stage III–IV) endometrial cancer (GOG #122), chemotherapy was reported to decrease abdominal and pelvic recurrence.23 Nevertheless, other studies showed that chemotherapy was not better than only radiotherapy or combined therapy and in fact chemotherapy resulted in lower survival when compared with these therapies.24,25 In our study, we found that the type of adjuvant therapy was not associated with 3-year PFS and 3-year DSS and that the site of recurrence was not related to the type of therapy. The reasons for this may be the limited number of patients and the unstandardized adjuvant therapy. However, performance of aggressive lymphadenectomy may also be considered as another reason. Sterilization of lymphatic sites with surgery and tumoral debulking may affect the efficiency of the adjuvant therapy. Treatment of the metastasis in the lymphatic regions with radiotherapy in case of insufficient surgery may be perceived as the increased efficiency of radiotherapy.
Retrospective design is the most important limitation of this study. Uniform adjuvant therapy could not be applied, and several types of combinations of platin-based chemotherapies were given as a result of the long study period. These were the other limitations of the study. However, this study is one of the rare studies having a large number of patients, which was conducted by a single institution.
In conclusion, the presence of recurrence is the only independent factor predicting DSS. The number of debulked metastatic lymph nodes and PA involvement predicted the likelihood of recurrence. Therefore, systematic lymphadenectomy should be part of the surgical treatment, and PA lymph nodes should be included in lymphadenectomy in patients with stage IIIC endometrial cancer. In addition, although the efficiency of systemic therapy could not be demonstrated in this study, stage IIIC endometrial cancer should be considered as a systemic disease because 70% of the recurrences were in extrapelvic regions and approximately 25% of the patients had nonnodal extrauterine disease. Therefore, multimodal treatment options seem to be appropriate. Nevertheless, more studies are needed for the standardization of the adjuvant therapies and elimination of the uncertainties.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Endometrial cancer; Stage IIIC; Recurrence