Abstract
Background: Endometrial carcinoma is the most common malignancy of the female genital tract and its incidence is increasing. However, treatment results have not improved during the last decades. Patients and Methods: Our regional quality register was used to evaluate treatment results for the period between January 1995 and December 2003. This study includes 2211 consecutive patients, of which 1993 surgically staged patients were evaluated in detail. Of these, 831 (53%) were at low risk and were given no further treatment after primary surgery. Patients with moderate- and high-risk tumors were postoperatively treated according to the respective protocols of one Swedish and one international study. Postoperative vaginal brachytherapy +/- external radiation was given to 486 (31%) patients at moderate risk, while 234 (15%) had high-risk disease and were randomized to external radiation + brachytherapy or external radiation + brachyterapy + chemotherapy. Results: Overall cause-specific 5- and 10-year survival was 83.9% and 81.3%, respectively, for all included patients. The corresponding figures for surgically staged patients were 87.4% and 84.9%, respectively. One important observation was that there was no significant difference in survival between patients at low and moderate risk. Conclusion: The results strongly suggest that the risk groups used during this study period were not optimal. It is recommended to use smaller, better specified groups defined by more prognostic factors for enhanced individualization of treatment.
Endometrial cancer is the most common malignancy of the female genital tract and its incidence is increasing. However, treatment results have not improved during the last decades. Despite the favorable prognosis for about 75% of the patients, the majority of whom have stage I and G1 tumors, a significant proportion of these women at low risk will die from their disease (1).
Tumor stages, degree of myometrial invasion and histological grade and type have proved to be of prognostic value with regard to the risk of recurrence and also to the long-term survival rate. The accuracy and validity of these factors are not especially high, however. Several studies have been conducted to test these prognostic factors, in which the patients were divided into two or three risk groups, defined by prognostic factors, and were treated with different treatment modalities (2, 3). The usefulness of these risk groups in large population-based studies has not yet been evaluated.
Moreover, it is surprising that no consensus exists as to the optimal management of this most common female malignancy of the lower abdomen. There is no agreement concerning the indications for lymph node surgery or adjuvant radiation therapy. The morbidity associated with whole pelvis radiation is considerable and this treatment should be reserved for patients at significant risk of pelvic node metastases or patients with local recurrence (3, 4). In order to obtain a balanced strategy for radiation therapy, spread of the malignancy to the pelvic nodes must be confirmed even if it is unlikely that lymph node sampling in itself yields therapeutic benefit (4).
The aims of this study were to evaluate the usefulness of the routinely used large risk groups as a basis for treatment choice and to ascertain whether it is possible to identify the factors predicting less favorable prognosis.
Patients and Methods
Characterization of the study population. The Västra Götaland region in Western Sweden has a population of approximately 1.5 million. A new treatment program for endometrial carcinoma was introduced in this region in 1995. This program includes recommendations concerning criteria for diagnosis, treatment, appropriate information to patients and referral to the Regional Oncology Center, to which all patient data was reported. A regional quality register, designed according to FIGO criteria, was set up and used to evaluate the treatment program.
Incidence of endometrial carcinoma in Västra Götaland, Sweden, 1995 to 2003.
Primary surgery, usually total abdominal hysterectomy and bilateral salpingoophorectomy without lymph node dissection in most cases, was performed at five different Departments of Gynecology and Obstetrics. The surgical procedures were performed according to treatment protocols. Patients requiring postoperative treatment were referred to the Department of Gynecologic Oncology, Sahlgrenska University Hospital, Göteborg.
Patients. All women diagnosed with endometrial cancer in the Västra Götaland region during 1995-2003 were initially included in the study. During the nine-year observation period, the incidence increased from 214 to 267 (Table I). This part of the study consists of 2211 consecutive patients with endometrial carcinoma diagnosed in the region between January, 1995 and December, 2003. The median and mean age at diagnosis were 68 (30-92) and 68 years old, respectively. Thirteen patients diagnosed at autopsy were excluded as were those 16 patients who were not included in the quality register. Of the remaining 2182 patients, 189 did not undergo primary surgery and were therefore excluded from further statistical analysis. The other 1993 patients underwent primary surgery and were postoperatively divided into three different risk groups.
The study was approved by the Göteborg regional ethics committee.
Surgically treated patients. Out of 1993 patients, 719 had Grade 1 (36%), 897 Grade 2 (45%) and 355 Grade 3+ undifferentiated tumors (18%). Tumor grade for 22 patients (1%) was not reported to the quality register.
Histologically, 1853 (93%) tumors were classified as endometroid adenocarcinomas. Sixty-one patients (3%) had clear cell carcinoma and 70 (4%) had UPSC. Nine patients had indefinable (no reported) histology (0.4%). All tumors were re-reviewed by one pathologist. Concerning age, 896 patients (45%) were 70 or older and 1097 (55%) were less than 70.
Definition of DNA ploidy status. DNA ploidy status was defined according to Hiddeman et al. (5). Tumor samples with one DNA stemline were classified as diploid and those with more than one cell population as non-diploid. A peak located within a certain DNA index (DI) range (0.95-1.04) was an additional criterion for classification as diploid in some cases. About one half of analyses were done using frozen tumor samples whereas paraffin-embedded material was used for the other half, primarily in the case of small tumors. Diploid tumors were found in 1097 patients (55%), whereas 682 (34%) had non-diploid tumors. DNA analysis was not performed in 214 (11%) cases.
Number of patients in different risk groups.
Treatment groups. Depending on surgical stage, histopathological subgroup and DNA ploidy status, the patients were divided into three different treatment groups. No further treatment was given to stage I patients with G1 or G2 tumors, infiltration of less than 50% of the uterine wall and diploid DNA (841 low-risk patients, 42.2% of the total). If one of the following criteria was present the patients were randomized to vaginal brachytherapy +/- external radiation (included in a Swedish national study reported IGCS, Bangkok, 2008 (6); 586 moderate-risk patients, 29.4% of the total): G3 (+undifferentiated), infiltration of more than 50% of the uterine wall or aneuploidy. In the case of two or three of the above-mentioned risk factors, the patients were randomized to external radiation + brachytherapy or external radiation + brachytherapy + chemotherapy (included in an international study on high-risk patients (7); 450 high-risk patients, 22.6% of the total). One hundred sixteen patients (5.8%) were not reported in the quality registry.
Statistical methods. Both univariate and multivariable survival analysis were performed for all the variables of interest in order to estimate hazard ratios of death from endometrial cancer, with 95% confidence intervals. Assuming proportional hazards between levels of the variables of interest, a multivariate proportional hazards regression (Cox regression) was performed using the PHREG procedure in SAS software. The multivariate analysis included age, histopathological diagnosis, grade, stage (with subgroups, where two categories of the stage variable consisted of two combined categories - stage IIIb together with IIIc and IVa together with IVb) and ploidy. Only deaths classified as being due to the cancer were considered to be events (“cause-specific survival”). A p-value below 0.05 was regarded as a significant result. The live table procedure in SAS software was used to generate survival graphs. All analyses were performed using SAS software version 9.1 (SAS Institute, Carey, NC, USA).
Results
All patients
Survival. Overall cause-specific survival for patients reported to the quality register was 83.9% and 81.3% at 5 and 10 years, respectively.
Results of univariate and multivariate proportional hazards regression.
Surgically staged patients
Distribution. There were 1573 stage I patients (79%), 179 stage II patients (9%), 182 stage III patients (9%) and 53 stage IV patients (3%). The stage was not reported in six cases (0.3%).
Survival. Overall cause-specific survival for surgically treated patients was 87.4% and 84.9% at 5 and 10 years, respectively. The 5-year survival for the low-, moderate- and high-risk groups was 97.4%, 94.9% and 83.0%, respectively, whereas 95.9%, 93.7% and 78.0% of the patients survived 10 years, respectively (Figure 1). There was no significant difference in survival between the low- and moderate-risk groups. However, survival in high-risk patients was significantly lower (p=0.0001) than in moderate-risk patients.
The number of relapses during the observation period was 40 among 827 low-risk patients (4.8%), 29 among 485 moderate-risk patients (6%) and 42 among 234 high-risk patients (18%).
Causes of death. The cause of death was endometrial carcinoma in 231 patients who did not survive 5 years (50%). Intercurrent disease was the cause of death in 162 cases (35%), whereas 57 patients had other malignant diseases (12.3%). Cause of death was not reported for 10 patients (2.3%).
Prognostic factors. In the univariate analysis all of the analyzed variables, such as age, histopathology, grade, surgical stage and DNA ploidy, had significant impact on survival. These results, related to variables analyzed in the univariate regression, are shown in Table III and Figures 2, 3, 4, 5, 6. The multivariate regression analysis showed that age, tumor type, grade and stage (except substages Ia, Ib and Ic) had a significant effect on survival. In this analysis, DNA ploidy was of limited prognostic value; however, as seen in Table III, it is not completely without importance.
Discussion
This study we analyzes a population-based, surgically staged endometrial carcinoma material. An important finding was revealed by the survival analysis of different risk groups. Surprisingly, no significant differences were observed between survival in the low-risk group and the intermediate-risk group. A 97.4% 5-year survival rate was found in the low-risk group and 10-year survival in the same group was 95.9% . Although these figures are acceptable, patients in surgical stage I with G1 or G2 tumors, myometrial infiltration less than 50% and diploid DNA should have better survival. On the other hand, patients in the intermediate-risk group had relatively good survival. These patients were included in a Swedish protocol, aimed at analyzing the role of postoperative external radiation on survival. It is believed that the postoperative radiation treatment (brachytherapy +/- external radiation) contributed to the good survival results in the intermediate-risk group. However, many of these patients were overtreated, with some side effects as a consequence of external beam radiation. Postoperative brachytherapy alone should result in the same survival rates for a majority of these patients (8). These results strongly suggest that the risk groups constituting a basis for treatment during this study period were too large and unspecific. Utilizing more prognostic factors, such as age, p53 (9), LV (10) and probably S-phase for diploid tumors, it would be possible to divide patients into smaller, better specified risk groups so that the selected therapy for each group would be better adapted to the individual patient.
Survival, according to risk group, in 1546 patients.
Survival, according to age, in 1987 patients.
Survival, according to histopathological diagnosis, in 1978 patients.
Survival, according to tumor grade, in1965 patients.
Survival, according to tumor stage, in 1973 patients.
A similar opinion was recently presented by GOG (4). During the course of the study, the authors divided the intermediate-risk group into “high” and “low” intermediate-risk groups, based on revaluated risk of recurrence. The study showed that patients in the “high” intermediate-risk group may have benefited from adjuvant radiotherapy whereas patients in the “low” intermediate-risk group did not. That paper further supports the findings of this study.
Cause-specific survival in the whole patient material was good, 83.9% at five years and 81.3% at 10 years. The corresponding figures for surgically staged patients were 87.4% and 84.9%, respectively. In comparison, Minelli et al. (11) recently published relative survival rates for a relatively large population (347 patients) from the Umbria region in Italy. In their material, the 5-year relative survival for the period 1978-1982 was 83% and 10-year survival was 80% . Based on <20% of the national population, the EUROCARE II study (12) presented an 82.9% 5-year relative survival rate for Sweden during 1987-1989. During the same period, Iceland reported 83.3%, and the Netherlands (also based on <20% of the national population) reported 83.4% 5-year relative survival. Unfortunately, newer population-based studies exclusively on surgically staged patients with which to compare the cause-specific survival in this study could not be found.
Survival, according to DNA ploidy, in 1774 patients.
Non-endometroid endometrial carcinomas make up about 10% of all endometrial cancers. However, these tumors account for more than 50% of recurrences and deaths from endometrial cancer (13). In this study, 93% of all cases were endometroid endometrial carcinomas. The somewhat lower incidence of non-.endometroid tumors in this material was probably due to the 172 (8%) excluded patients, the majority of whom were in poor condition, and therefore did not undergo primary surgery. This selection may partly contribute to the high cause-specific survival presented here.
Other prognostic factors analyzed in this study were present to the same extent as in other large study populations (1), and did not contribute to any surprising results.
In summary, this population-based study of surgically staged endometrial cancer shows good 5- and 10-year survival rates in western Sweden. It is concluded that better specified and smaller risk groups in the treatment programs would further increase the survival of these patients
- Received September 30, 2008.
- Revision received January 23, 2009.
- Accepted February 16, 2009.
- Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
