Endometrial cancer is the most common gynecologic malignancy in developed countries, with an estimated 39,000 and 1,000 newly diagnosed cases in the United States and Austria, respectively. Although many patients are diagnosed with an early stage disease, 7,400 deaths will occur.1 Approximately 90% of women with endometrial cancer, however, have abnormal uterine bleeding as the only presenting complaint, and this providentially leads to early diagnosis in most cases.2
The diagnosis of an endometrial cancer is suspected in patients with a postmenopausal bleeding or a thickened endometrium measured by transvaginal ultrasonography. Outpatient endometrial biopsy, hysteroscopy with directed biopsy, or hysteroscopy with dilation and curettage (D&C) are diagnostic tests to confirm or rule out endometrial cancer in clinical routine.3,4
In Austria, performing hysteroscopy with D&C is the standard of clinical care in the management of patients with postmenopausal bleeding or suspicious endometrium. It has been shown that patients after D&C and hysteroscopy have an increased rate of positive peritoneal washings and therefore higher International Federation of Gynecology and Obstetrics (FIGO) tumor stage at subsequent hysterectomy.5,6 In other gynecologic malignancies such as ovarian7–9 and cervical10 cancer, the time interval between diagnosis and onset of therapy, ie surgery or chemotherapy, has been shown to be a significant prognostic factor. Few data are available for patients with endometrial cancer.11
The aim of the present multicenter study was to evaluate whether a prolonged time interval between hysteroscopy, D&C, and hysterectomy has an effect on survival in patients with surgically treated endometrial cancer.
MATERIALS AND METHODS
Clinical data were obtained retrospectively from files at the Departments of Obstetrics and Gynecology at Medical University of Vienna, the Landeskrankenhaus Klagenfurt, and the Innsbruck Medical University. Three hundred forty-four consecutive patients (Medical University of Vienna 168, Landeskrankenhaus Klagenfurt 74, Innsbruck Medical University 102) with histologically confirmed endometrioid endometrial cancer undergoing surgery between December 1995 and January 2005 were included in our study. Other histologic types of endometrial cancer were excluded from the present study. Approval for this study was obtained by the respective institutional review boards.
Diagnosis of endometrial cancer was established by D&C. Subsequently, patients were treated by hysterectomy, bilateral salpingo-oophorectomy, pelvic, and in selected cases by paraaortic lymphadenectomy (n=116). In cases of lymph node metastases, postoperative radiotherapy was applied according to standardized treatment protocols. A regimen of adjuvant chemotherapy using carboplatin/paclitaxel was used in patients with advanced disease (n=37). Histologic staging and grading was performed according to the current FIGO classification.
In all participating centers, patients were followed up at regular intervals after surgery, including inspection, vaginorectal, and screening for serum tumor marker evaluation. In cases of clinically suspicious findings or tumor marker elevation, computed tomography was performed.
After testing for normality using Kolmogorov-Smirnov tests, values are given as mean (standard deviation) or median (interquartile range) where appropriate. Measures were compared using Student t test, Mann-Whitney U test, or analysis of variance with a multiple comparison procedure for pair-wise comparisons, where appropriate. Linear associations of continuous parameters were measured using Pearson correlation analysis. Survival probabilities were calculated by a univariable Cox regression analysis (metric variables) or a product limit method of Kaplan and Meier using the log rank test (categorical variables). A multivariable Cox regression model was performed comprising tumor stage (FIGO I compared with II compared with III compared with IV), tumor grade (G1 compared with G2/G3), patients' age at diagnosis (metric values), and time interval from curettage to surgery (first quartile compared with second quartile compared with third quartile compared with fourth quartile) as previously decribed.9 The results were analyzed for the endpoint of disease-free and overall survival. Survival times of patients disease-free or still alive were censored with the last follow-up date. Values of P less than 0.05 were considered statistically significant. We used the statistical software SPSS 11.0 for Windows (SPSS Inc., Chicago, IL) for statistical analysis.
Patients' characteristics are shown in Table 1. Within the study period, we did not observe any differences in the frequency of use of hysteroscopy (P=.8). The distribution of FIGO stages was similar in patients with and without hysteroscopy (P=.8). In five patients, hysterectomy was delayed 3 months or more. Time intervals among the three centers were statistically different (30.4 days compared with 32.3 days compared with 18.9 days, P<.001). We did not find any association between the length of the time interval between D&C and hysterectomy and FIGO tumor stage (P=.2), tumor grade (P=.9), or patients' age at diagnosis (P=.8). In a Kaplan-Meier analysis, FIGO tumor stage, tumor grade, patients' age at diagnosis, but not center and time interval from D&C to hysterectomy were associated with disease-free and overall survival (Table 2). In a multivariable Cox regression model, tumor stage, tumor grade, and patients' age but not center and time interval between D&C and hysterectomy were associated with a shortened disease-free and overall survival (Table 2).
Few data are available on the effect of treatment delay in endometrial cancer. Performing diagnostic hysteroscopy and D&C, as the standard of care in the diagnosis of endometrial cancer in Austria, has been shown to be associated with an increased risk for malignant cells in the peritoneal lavage performed at subsequent hysterectomy. A possible adverse influence of this suspected tumor cell spillage to the abdominal cavity has been hypothesized.
It can reasonably be speculated that the longer the time from D&C to definite surgery, the higher risk that malignant cells within the abdominal cavity will attach to the peritoneum, invade, start malignant growth, and impair survival. A similar finding has been shown in ovarian cancer.7 We present a study with respect to the prognostic value of the time interval between D&C and hysterectomy in endometrial cancer.
In the present study, we did not ascertain any significant association between the length of time interval between D&C and hysterectomy and FIGO tumor stage, including the rate of positive peritoneal cytology, tumor grade, and patients' age. Our study adds further evidence that diagnostic hysteroscopy performed before or during D&C does not alter FIGO stage distribution. Furthermore, differences in the interval between D&C and hysterectomy had no significant effect on disease-free and overall survival.
Our study has several biases, including its retrospective design. A number of factors might have influenced the length of the time interval between D&C and hysterectomy, such as patients' comorbidities, availability of surgeons and operating room vacancies, patients' preferences, etc. Although we performed multivariable analysis, we cannot control for these factors. Furthermore, studies in patients with endometrial cancer are often weakened by the good prognosis of the disease and the subsequent low number of events. Therefore, we cannot exclude a small effect of the length of time interval on survival. However, clinical significance seems unlikely. The absence of patients with a wider interval and the absence of a cutoff time might be seen as further shortcomings. The strengths of our study are the multicenter study design and the relatively large series of patients.
It can be argued that the results of our present study do not help physicians in patient counseling and management, because most time intervals were relatively short, and irrespectively, patients and doctors alike are going to schedule surgery for the next available opening in the operating room schedule. However, histologic diagnosis of endometrial cancer often takes 5–7 days, preoperative tests and scheduling for surgery might take several weeks. Patients are often anxious due to the seemingly long interval between D&C and hysterectomy. Our data provide evidence to reassure affected patients.
In the present study, we were not able to show that a prolonged time interval between D&C and hysterectomy has a significant effect on the prognosis of patients with endometrial cancer. Based on our results, it is unlikely that the time interval between hysteroscopy and D&C and subsequent hysterectomy significantly affects survival of patients with endometrial cancer.
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© 2008 The American College of Obstetricians and Gynecologists
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