Background and Objective: There is marked controversy regarding optimal management patients with stage IB grade III endometrial carcinoma. The present study analyzes the current practices regarding adjuvant radiation therapy for those patients in our institute and also assessed prognostic factor affecting overall survival outcome. Patients and Methods: A total 66 patients with postoperative FIGO stage 1B, grade III endometrial carcinoma were treated and evaluated between the years 2009 and 2014. Risk factors assessed age (<60 versus ≥60), tumor size (≤4 cm versus >4 cm), site of primary tumor (involvement of lower uterine segment versus no involvement), Lymphaden e ctomy (performed versus not performed), Lymph-vascular space invasion (positive or negative), type of surgery performed (less than total abdominal hysterectomy and bilateral salpingo-ophorectomy (TH/BSO) versus greater than or equal TH/BSO), radiation sequence with surgery (no radiation versus adjuvant radiation), and type of radiation (pelvic external beam radiotherapy versus vaginal brachytherapy versus both). Results: Adjuvant radiation therapy after surgery was associated with significantly better time to relapse (p = 0.001) in comparison to those patients who underwent surgery alone. There was statistically significant improvement of survival of patients who received adjuvant radiation therapy in comparison with those who underwent surgery alone. There was no statistically significant difference in relapse between external pelvic radiotherapy, brachytherapy and both (p = 0.161). There was no statistically significant difference in overall survival between different types of adjuvant radiation therapy (p = 0.318). Adjuvant radiation therapy (HR 0.173, 95% CI 0.049 - 0.609, p = 0.006) and tumor size (HR 4.065, 95% CI 1.120 - 14.761, p = 0.033) were the only statistically significant predictors for relapse in multivariate analysis. Adjuvant radiation therapy (HR 0.159, 95% CI 0.045 - 0.563, p = 0.004), age (HR 10.357, 95% CI 1.195 - 89.746, p = 0.034) and lymphadenectomy (HR 0.240, 95% CI 0.071 - 0.811, p = 0.022) were statistically significant predictors for overall survival. Conclusion: The current study suggested that adjuvant radiation therapy definitely improve survival of patients with stage IB, grade III endometrial cancer. There is a need for more randomized trials to define patients who require adjuvant radiation therapy and define what type of radiation should be received. Well defined guidelines are very important to standardize treatment and cut costs in clinical practice.
Endometrial cancer is the most sixth common neoplasm in women worldwide [
Endometrial carcinoma has been classified into two main clinic-pathological and molecular types; type I is the most common (80% - 90%) endometrioid adenocarcinoma and type II consists of non endometrioid subtypes (10% - 20%) such as clear cell, serous and undifferentiated carcinomas in addition carcinosarcoma/malignant-mixed Mullerian tumor [
Histopathologically, endometrioid is classified into three grades; 1, 2 and 3. Due to high possibility of local recurrence, lymph node and distant spread, grade 3 is considered high grade [
In accordance with FIGO (The International Federation of Gynecology and Obstetrics) staging for endometrial cancer, stage 1 disease was further sub classified depending on the depth of tumor invasion because this is considered to be an adverse risk factor for disease outcome. In 2009, FIGO staging updated the previous 1988 version. Stage I subdivided into Stage IA included tumors with less than 50% myometrial invasion and stage IB included tumors with more than 50% myometrial invasion, with omission of stage IC, which previously included tumors with more than 50% myometrial invasion. Therefore, prior stage IC is equal to the current stage IB [
Patients with stage I endometrial cancer is mainly treated with surgery. Because of low risk of local recurrence and distant metastasis, surgery alone with or without vaginal brachytherapy is often the treatment of choice of stage IA with excellent outcomes [
Outcome of patients with stage IB widely differ. Their outcome depends on grade of tumor and presence or absence of risk factors which previously identified in large prospective trials, including age, tumor size and lymphovascular space invasion (LVSI) [
Treatment recommendation of the major evidenced based guidelines on endometrial cancer is heterogeneous. For example, The American Society of Clinical Oncology/American Society for Radiation Oncology (ASCO/ASTRO) guidelines recommended adjuvant external beam radiation therapy to the pelvis for all patients with stage IB grade III. Furthermore, they recommended with limited evidence addition of vaginal brachytherapy after external pelvic irradiation [
The European Society for Medical Oncology/European Society for Radiotherapy and Oncology/European Society of Gynecological Oncology (ESMO/ESTRO/ESGO) guidelines suggest that vaginal brachytherapy may be an alternative to external pelvic radiation therapy. Their recommendation for adjuvant external pelvic radiation is only category B (moderate or strong evidence for efficacy but with limited clinical benefit, generally recommended) [
Finally, recommendation of the National Comprehensive Cancer Network (NCCN) Guidelines is according to presence or absence of risk factors. They recommend vaginal brachyrherapy with or without external pelvic radiation therapy for stage IB grade III with absence of adverse risk factors or observation. Their recommendation of observation is category 2B based upon lower level evidence but there is NCCN consensus that intervention is appropriate. On contrary they recommended external pelvic radiation therapy with or without vaginal brachytherapy for patient with adverse risk factors. Furthermore addition of chemotherapy is category 2B recommendation [
Accordingly, there is marked controversy regarding optimal management patients with stage IB grade III endometrial carcinoma. The present study analyzes the current practices regarding adjuvant radiation therapy for those patients in our institute and also assessed prognostic factor affecting overall survival outcome.
After approval by Institutional Review Board of Mansoura faculty of Medicine (IRB-MFM), this is retrospective study was conducted in clinical oncology& nuclear medicine, Mansoura University. A total 66 eligible patients with postoperative FIGO stage 1B, grade III endometrial carcinoma were treated and evaluated between the years 2009 and 2014.
The current analysis is limited to the years following 2009 when the new FIGO staging system was applied. Patients with stage IC (according to the old staging system) were also included which is equal to current stage IB.
Inclusion criteria:
Patients of any age with a histologically proven endometrioid carcinoma postoperative FIGO stage IB grade 3 were eligible for the study (stage IB included tumors with more than 50% myometrial invasion). Poorly or un-differentiated endometrioid carcinomas were also included in our analysis.
Exclusion criteria:
Patients for whom the radiation sequence with surgery was unknown or lost follow up also excluded from the study.
Study objectives:
The primary objective of this study is compared each type of treatment received to stage IB, grade III endometrial carcinoma.
Risk factors assessed age (<60 versus ≥60), tumor size (≤4 cm versus >4 cm), site of primary tumor (involvement of lower uterine segment versus no involvement), Lymphadenectomy (performed versus not performed), Lymph-vascular space invasion (positive or negative) type of surgery performed (less than Total abdominal hysterectomy and bilateral salpingo-ophorectomy (TH/BSO) versus greater than or equal TH/BSO), radiation sequence with surgery (no radiation versus adjuvant radiation), and type of radiation (pelvic external beam radiotherapy versus vaginal brachytherapy versus both).
Follow up:
Chest X-ray and abdominal-pelvic CT or MRI were conducted every six months for the first two years post-surgery and then annually.
Statistical analysis:
Data were entered and analyzed using IBM-SPSS software (Version 25.0. Armonk, NY: IBM Corp.). Qualitative data were expressed as frequency and percentage. Quantitative data were initially tested for normality using Kolmogorov-Smirnov and Shapiro-Wilk’s test with data being normally distributed if p > 0.050. Quantitative data were expressed as mean ± standard deviation (SD). Qualitative data were compared by Chi-Square test (or Fisher’s exact test). Monte Carlo significance was used when appropriate. Bonferroni method to adjust p values when comparing column proportions was also used. Quantitative data between two groups were compared by Independent-Samples t-test if data were normally distributed in both groups. The non-parametric alternative Mann-Whitney U test was used if not. Quantitative data between more than two groups were compared by One-way ANOVA test if data were normally distributed in all groups. The non-parametric alternative Kruskal-Wallis H test was used if not. Pairwise comparisons were performed if the result was significant to detect where that significant difference existed. The Kaplan-Meier method was used to estimate the probability of survival past given time points (i.e. it calculates a survival distribution). The survival distributions of two or more groups of a between-subjects factor can be compared for equality using log-rank test. Cox regression analysis was used to predict survival. For any of the used tests, results were considered as statistically significant if p value ≤ 0.050.
This study included 66 patients with stage IB grade III endometrial carcinoma with mean age ± SD of 60.6 ± 6.1 years. Most of the patients underwent total abdominal hystrectomy and bilateral salpingo-oophrectomy, only 7.6% of patients underwent substandard surgery. Thirty seven tumors (56.1%) were larger than 4 cm. Twenty six tumors (39.4%) showed involvement of lower uterine segment. Most of the patients (74.2%) underwent lymphadenectomy. Lymphovascular space invasion (LVSI) was present in 34.8% of tumors, absent in 42.4% of tumors and not assessed in 22.7% of tumors. Twenty patients (30.3%) did not receive adjuvant radiation therapy. 46 patients (69.7%) received adjuvant radiation therapy. Among those patients, 16 (24.2%) received external pelvic radiation, 14 (21.2%) received brachytherapy, and 16 (24.2%) received both (brachytherapy and external pelvic radiation). Fourteen patients (21.2%) had relapse, ten of them (15.1%) were pelvic relapse and four patients (6.1%) presented with vaginal relapse (
Variable | Frequency | Percentage |
---|---|---|
Age category: | ||
<60 years | 26 | 39.4% |
≥60 years | 40 | 60.6% |
Surgery type: | ||
TAH & BSO | 61 | 92.4% |
Subtotal hysterectomy | 5 | 7.6% |
Tumor size: | ||
≤4 cm | 37 | 56.1% |
>4 cm | 29 | 43.9% |
Lower uterine segment: | ||
Involved | 26 | 39.4% |
Not involved | 40 | 60.6% |
Lymphadenectomy: | ||
Done | 49 | 74.2% |
Not done | 17 | 25.8% |
Lymphovascular space invasion: | ||
Present | 23 | 34.8% |
Absent | 28 | 42.4% |
Not assessed | 15 | 22.7% |
Post-operative treatment type: | ||
No adjuvant radiation therapy | 20 | 30.3% |
Adjuvant radiation therapy | 46 | 69.7% |
Type of adjuvant radiation therapy: | ||
External pelvic radiotherapy | 16 | 24.2% |
Vaginal brachytherapy | 14 | 21.2% |
Both | 16 | 24.2% |
Relapse: | ||
Yes | 14 | 21.2% |
No | 52 | 78.8% |
Site of relapse: | ||
Pelvic | 10 | 15.1% |
Vaginal | 4 | 6.1% |
TAH & BSO total abdominal hysterectomy and bilateral salpingo-ophrectomy.
There were no statistically significant difference in any of clinic-pathological factors tested between patients who underwent surgery alone and those who received adjuvant radiation therapy. Relapse was statistically significantly higher in patients who underwent surgery alone (
Disease outcome:
Survival outcome of 66 patients with Stage IB grade III endometrial carcinoma were analyzed. After median follow up period 50 months (range 9 - 72 month). Fourteen patients were died from endometrial cancer at the end of follow up.
Variable | Treatment arm | χ2 | p value | |
---|---|---|---|---|
Surgery (n = 20) | Surgery and adjuvant radiation therapy (n = 46) | |||
Age category: | 0.232 | 0.630 | ||
<60 years | 7 (35%) | 19 (41.3%) | ||
≥60 years | 13 (65%) | 27 (58.7%) | ||
Surgery type: | 2.352 | 0.312* | ||
TAH + BSO | 20 (100%) | 41 (89.1%) | ||
Subtotal hysterectomy | 0 (0%) | 5 (10.9%) | ||
Tumor size: | 0.428 | 0.513 | ||
≤4 cm | 10 (50%) | 27 (58.7%) | ||
>4 cm | 10 (50%) | 19 (41.3%) | ||
Lower uterine segment: | 0.004 | 0.947 | ||
Involved | 8 (40%) | 18 (39.1%) | ||
Not involved | 12 (60%) | 28 (60.9%) | ||
Lymphadenectomy: | 0.497 | 0.481 | ||
Done | 16 (80%) | 33 (71.74%) | ||
Not done | 4 (20%) | 13 (28.26%) | ||
Lymphovascular space invasion: | 4.982 | 0.097** | ||
Present | 3 (15%) | 20 (43.48%) | ||
Absent | 11 (55%) | 17 (36.96%) | ||
Not assessed | 6 (30%) | 9 (19.56%) | ||
Relapse: | 9.716 | 0.003* | ||
Yes | 9 (45%) | 5 (10.9%) | ||
No | 11 (55%) | 41 (89.1%) |
Data are expressed as frequency (percentage). p value by Chi-Square test, *Fisher’s Exact test, or **Monte Carlo significance test.
Adjuvant radiation therapy after surgery was associated with significantly better time to relapse (p = 0.001) in comparison to those patients who underwent surgery alone (observation group) (
Log-Rank was used for comparing time to relapse and overall survival between different types of adjuvant radiation therapy. There was no statistically significant difference in relapse between external pelvic radiotherapy, vaginal brachytherapy and both (p = 0.161) (
Cox regression analysis of factors potentially affected relapse was done. The following factors were analyzed, treatment received, age, type of surgery, tumor size, lymphadenectomy and lymphovascular space invasion (LVSI). In univariate analysis, treatment (surgery alone versus surgery and adjuvant radiation therapy) (HR 5.437, 95% CI 1.810 - 16.332, p = 0.003) and tumor size (≤4 cm, >4 cm) (HR 3.942, 95% CI 1.234 - 12.587, p = 0.021) were the only statistically significant factors. Also in multivariate analysis; treatment (HR 0.173, 95% CI 0.049 - 0.609, p = 0.006), tumor size (HR 4.065, 95% CI 1.120 - 14.761, p = 0.033) and lymphadenectomy (HR 0.270, 95% CI 0.078 - 0.933, p = 0.039) were the only statistically significant predictors for relapse (
Cox regression analysis of factors potentially affected overall survival was done. The following factors were tested, treatment received, age, tumor size, tumor site and lymphadenectomy. In univariate analysis, treatment (surgery alone versus surgery and adjuvant radiation therapy) (HR 4.006, 95% CI 1.329 - 12.069, p = 0.014), age (HR 13.518, 95% CI 1.694 - 107.901, p = 0.014) and tumor size (HR 3.896, 95% CI 1.219 - 12.455, p = 0.022) were statistically significant factors for overall survival. In multivariate analysis; treatment (HR 0.159, 95% CI 0.045 - 0.563, p = 0.004), age (HR 10.357, 95% CI 1.195 - 89.746, p = 0.034) and lymphadenectomy (HR 0.240, 95% CI 0.071 - 0.811, p = 0.022) were statistically significant predictors for overall survival (
variable | Univariate analysis | Multivariate analysis | ||||
---|---|---|---|---|---|---|
HR | 95% CI | p value | HR | 95% CI | p value | |
Treatment: Surgery Surgery and adjuvant radiation | 5.437 | 1.810 - 16.332 | 0.003 | 0.173 | 0.049 - 0.609 | 0.006 |
Age: ˂60 years ≥60 years | 1.879 | 0.589 - 5.994 | 0.287 | 1.161 | 0.287 - 4.701 | 0.835 |
Type of surgery: TAH + BSO Subtotal surgery | 0.866 | 0.110 - 6.421 | 0.866 | 0.718 | 0.142 - 3.638 | 0.689 |
Tumor size: ≤4 cm ˃4 cm | 3.942 | 1.234 - 12.587 | 0.021 | 4.065 | 1.120 - 14.761 | 0.033 |
lower uterine segment: Involved Not involved | 0.867 | 0.301 - 2.500 | 0.792 | 0.754 | 0.216 - 2.632 | 0.657 |
Lymphadenectomy: Done Not done | 0.399 | 0.138 - 1.150 | 0.089 | 0.270 | 0.078 - 0.933 | 0.039 |
LVSI: Abscent Present | 0.781 | 0.220 - 2.769 | 0.702 | 0.783 | 0.188 - 3.270 | 0.738 |
variable | Univariate analysis | Multivariate analysis | ||||
---|---|---|---|---|---|---|
HR | 95% CI | p value | HR | 95% CI | p value | |
Treatment: Surgery Surgery and adjuvant radiation | 4.006 | 1.329 - 12.069 | 0.014 | 0.159 | 0.045 - 0.563 | 0.004 |
Age: ˂60 years ≥60 years | 13.518 | 1.694 - 107.901 | 0.014 | 10.357 | 1.195 - 89.746 | 0.034 |
Tumor size: ≤4 cm ˃4 cm | 3.896 | 1.219 - 12.455 | 0.022 | 2.675 | 0.786 - 9.105 | 0.115 |
lower uterine segment: Involved Not involved | 1.162 | 0.389 - 3.469 | 0.788 | 0.696 | 0.220 - 2.203 | 0.538 |
Lymphadenectomy: Done Not done | 0.413 | 0.143 - 1.194 | 0.102 | 0.240 | 0.071 - 0.811 | 0.022 |
FIGO stage I endometrial cancer circumscribes various group of cancers whose treatment is not well understood. Published GOG33 paper in 1987 assessed the surgical pathological features of stage I endometrial cancer patients [
After publication of GOG33, large randomized trials had been published evaluating the role of adjuvant radiation therapy in early stage endometrial cancer [
In these trials, patients were randomized after surgery (total abdominal hysterectomy and bilateral salpingo-ophorectomy) to external beam radiation therapy or observation. The three trials and meta-analysis by Kong et al. [
PORTEC-1 trial [
GOG99 trial [
MRC ASTEC trial [
Data from previous randomized trials provide strong evidence that adjuvant radiation therapy is improving local control, but not overall survival in patients with high grade deeply invasive stage I endometrial cancer. PORTEC-3 randomized trial was aiming to intensify treatment beyond radiation alone. The randomization was between adjuvant radiation therapy alone versus adjuvant chemotherapy and radiation therapy. PORTEC-3 trail included patients with stage IB grade III. The authors observed inferior survival outcome among those high risk patients. Only toxicity and quality of life data, but not survival outcome had been reported in this study [
The current study presents information on practice pattern regarding the use of adjuvant radiation therapy for stage I grade III endometrioid adenocarcinoma of the uterus. In this study, 30% of patients did not receive adjuvant radiation therapy. Similarly a recent study from National Cancer Data Base (NCDB) showed that 52% of patients with stage IB (any grade) did not receive adjuvant radiation therapy [
This finding suggests discrepancy between national guidelines and common practice. This may be explained heterogeneity in groups of patients included in the previous clinical trials and heterogeneity in the treatment arms, making it difficult to define exactly which patients would gain the benefit from adjuvant radiation therapy.
The current study showed adjuvant radiation therapy after surgery was associated with statistically significant better local control and improvement of survival in comparison to those patients who underwent surgery. Similar observation was reported by Harkenrider et al. [
On the other hand, several randomized trials and meta-analyses did not show improvement of survival [
The PORTEC-1 was planned to detect five years survival benefit of 10% for adjuvant external beam radiotherapy. This trial included around 700 patients, but given the low event rates, would have required more than 2000 patients per arm [
The current study observed that there was no statistically significant difference in relapse between external pelvic radiotherapy, vaginal brachytherapy and both. Also, there was no statistically significant difference in overall survival between different types of adjuvant radiation therapy. Similarly, PORTEC-2 trial stated that there was no difference in locoregional relapse or overall survival between vaginal brachytherapy and external beam radiotherapy for patients with endometrial cancer of high-intermediate risk [
The current study analyzed factors potentially affected relapse and overall survival. The prognostic value of positive peritoneal washing is debatable.
The majority of studies found that positive peritoneal washings were independent prognostic factor [
Multivariate analysis of factors potentially affected overall survival found that treatment (HR 0.159, 95% CI 0.045 - 0.563, p = 0.004), age (HR 10.357, 95% CI 1.195 - 89.746, p = 0.034) and lymphadenectomy (HR 0.240, 95% CI 0.071 - 0.811, p = 0.022) were statistically significant predictors for overall survival. Many studies showed that age is important predictor for survival [
Despite that this study is retrospective study with limited number of cases, it highlights the variation in the current practice in the management of patients with stage IB, grade III endometrioid carcinoma of the uterus. The current study suggested that adjuvant radiation therapy definitely improve survival of patients with stage IB, grade III. There is a need for more randomized trials to define patients who require adjuvant radiation therapy and define what type of radiation should be received. Well defined guidelines are very important to standardize treatment and cut costs in clinical practice.
The author declares no conflicts of interest regarding the publication of this paper.
Eladawei, G.E. (2019) Management of Stage IB Grade III Endometrial Cancer: Single Institute Experience. Journal of Cancer Therapy, 10, 290-304. https://doi.org/10.4236/jct.2019.104023