|Year : 2019 | Volume
| Issue : 4 | Page : 341-347
Analysis of postoperative radiotherapy effects within risk groups in patients with FIGO I, II, and III endometrial cancer
Vladan Popovic1, Neda Milosavljevic1, Marija Zivkovic Radojevic2, Radisa H Vojinovic3, Nikola Nedovic4, Slobodanka Mitrovic5, Jasmina Nedovic1, Aleksandar Tomasevic6
1 Center for Oncology and Radiology, Clinical Center Kragujevac, Kragujevac, Serbia
2 Center for Oncology and Radiology, Clinical Center Kragujevac; University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia
3 University of Kragujevac, Faculty of Medical Sciences; Department for Radiology, Clinical Center Kragujevac, Kragujevac, Serbia
4 University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia
5 University of Kragujevac, Faculty of Medical Sciences; Department for Pathology, Clinical Center Kragujevac, Kragujevac, Serbia
6 Department of Brachyterapy, Institute for Oncology and Radiology, Belgrade, Serbia
|Date of Web Publication||11-Oct-2019|
Marija Zivkovic Radojevic
Center for Oncology and Radiology, Clinical Center Kragujevac; University of Kragujevac, Faculty of Medical Sciences, Kragujevac
Source of Support: None, Conflict of Interest: None
INTRODUCTION: To define indications for adjuvant radiotherapy in patients with endometrial cancer, the risk groups have been established according to clinical and pathological prognostic factors. The purpose was to determine precise criteria for adjuvant radiotherapy and identify patients with increased risk for disease relapse who may benefit from postoperative radiotherapy, with an acceptable level of toxicity.
MATERIALS AND METHODS: A retrospective study was conducted at the Department of Oncology and Radiology, Kragujevac, during a 5-year period. A group of 80 patients with endometrial cancer treated with adjuvant radiotherapy were included in the study. Patients were divided into four risk groups according to ESMO-ESGO-ESTRO Consensus Conference classification. The Kaplan-Meier method was used for overall and progression-free survival. A statistical analysis was performed using SPSS 20.0 statistical software.
RESULTS: The 5-year survival rate was 80%, and 66.3% patients were progression-free during this period. Fatal outcome occurred in 20% of patients. The results showed survival was shortest in patients from the high-risk group. Factors that had impact on the 5-year survival were comorbidities, FIGO stage, postoperative radiotherapy, organ site of late toxicity, and localization of metastases. The analysis of postoperative radiotherapy effects showed that 72.5% of patients had no complications. The most common symptoms of late irradiation toxicity arose from the gastrointestinal tract. Toxicity was usually moderate.
CONCLUSIONS: Adjuvant radiotherapy can potentially prolong survival and prevent recurrence, with acceptable level of toxicity, to preserve patient's quality of life. Patient classification into appropriate risk groups allows for adjuvant treatment individualization.
Keywords: Adjuvant radiotherapy, endometrial carcinoma, radiotherapy effects
|How to cite this article:|
Popovic V, Milosavljevic N, Radojevic MZ, Vojinovic RH, Nedovic N, Mitrovic S, Nedovic J, Tomasevic A. Analysis of postoperative radiotherapy effects within risk groups in patients with FIGO I, II, and III endometrial cancer. Indian J Cancer 2019;56:341-7
|How to cite this URL:|
Popovic V, Milosavljevic N, Radojevic MZ, Vojinovic RH, Nedovic N, Mitrovic S, Nedovic J, Tomasevic A. Analysis of postoperative radiotherapy effects within risk groups in patients with FIGO I, II, and III endometrial cancer. Indian J Cancer [serial online] 2019 [cited 2020 Jul 9];56:341-7. Available from: http://www.indianjcancer.com/text.asp?2019/56/4/341/268958
Vladan Popovic and Neda Milosavljevic contributed equally to the study.
| » Introduction|| |
In most developed countries, endometrial cancer is one of the most common tumors in women., It predominantly occurs in postmenopausal women, but 5%–30% of women are diagnosed before 50 years of age. There are two types of endometrial cancer-estrogen-dependent and estrogen-independent types. The most common histopathological type is adenocarcinoma, accounting for 80% of cases.,,,, Risk factors for endometrial cancer are age (over 60 years), obesity, diabetes, hypertension, hyperthyroidism, early menarche and late menopause, larger number and longer duration of menstrual cycles, multiparity, infertility, irregular menstrual cycles due to lack of ovulation, presence of hormone-dependent breast cancer, etc.,,,,,,,,,, In 68% of newly-diagnosed cases, the disease is limited to uterus, whereas spread of extrauterine tumor in the absence of distant metastases can be found in 20% of patients. At the time of diagnosis, about 8% of patients have distant metastases.
Endometrial cancer treatment requires a multimodal approach, with initial surgical intervention in most cases. To strictly define indications for adjuvant therapy, risk groups have been established according to clinical and pathological prognostic factors. At the time of pathological diagnosis, about 90% of patients are in FIGO I or II (Federation Internationale de Gynecologie et d'Obstetrique) stage of the disease; thus, the precise criteria for adjuvant radiotherapy need to be established., The purpose of risk group definition is to identify patients with an increased risk of disease relapse who may benefit from postoperative radiotherapy, with an acceptable level of toxicity. Earlier studies have shown that adjuvant radiotherapy reduces the rate of local recurrence of the disease but without statistically significant impact on overall survival (OS).,, From the results of previous studies, ESMO-ESGO-ESTRO Consensus Conference classification of risk group is established, but complex factors that influence patient prognosis and OS are yet under investigation.
The aim of this study is to report adjuvant radiotherapy effects and 5-year survival for patients with operable endometrial cancer who are reclassified according to the ESMO-ESGO-ESTRO Consensus Conference classification for risk groups in adjuvant radiotherapy.
| » Materials and Methods|| |
A retrospective study was conducted from 2012 to 2017 at the Department of Oncology and Radiology, Clinical Center Kragujevac, with the approval of the institutional Ethics Committee. The study analyzed socio-demographic data, personal and family history, and treatment data obtained from the medical records for all patients who met the study inclusion criteria.
The inclusion criteria were diagnosis and histopathological confirmation of endometrial cancer, FIGO stage I-III, in patients 30–80 years of age, in good general condition performance status 0–2 (Eastern Cooperative Oncology Group Performance Status, ECOG PS), who underwent standard surgical hysterectomy with bilateral adnexectomy, received postoperative radiotherapy 4–6 weeks following surgery, and had complete medical records available. The exclusion criteria were unknown stage/grade, systemic chemotherapy application, previous pelvic radiotherapy, and radiotherapy initiated more than 7 weeks after surgery.
Initially, 365 patients were identified. After eliminating patients with incomplete medical records, 80 patients who met all the inclusion criteria and none of the exclusion criteria were enrolled into the study. These 80 patients were divided into four risk groups according to the recommendations of the ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer.
We have analyzed OS and progression-free survival (PFS–starting from the date of surgery until the date of the last follow-up or death outcome), occurrence and localization of tumor recurrence, and distant metastases. The histopathological type of tumor and the following variables were also examined as factors that may influence prognosis and 5-year survival: age, place of residence, smoking, alcohol consumption, family history (heredity), number of deliveries and abortions, oral contraceptive use, intrauterine devices, tamoxifen use, and menopause at the time of diagnosis. Further, an analysis of radiotherapy modalities (number of fractions, radiation dose administered) and late irradiation toxicity, according to radiation therapy oncology group recommendations, was performed. Reported toxicity symptoms were graded retroactively.
Procedure for external beam radiotherapy
Adjuvant radiotherapy treatment was planned for all patients on an X-ray simulator and conducted on the linear accelerator, in a 5-day regimen, with parallel opposing pelvic fields (2D technique), using 10 MV energy. In cases where the patient's anterior/posterior (AP) diameter was less than 20 cm and 6 MV energy was used.
External beam radiotherapy dose ranged from 36 Gy to 46 Gy, with standard fractionation regimen (1.8–2 Gy\day). When there was a CT- or MRI-verified para-aortic lymphadenopathy, the patients were treated with extended fields, with dose of 45 Gy, according to imaging data, or limits determined as follows: the upper border on the first lumbar vertebral body (L1), the upper edges of the standard pelvic field, and tops of vertebral transverse processes (giving the average field of 8 cm).
The brachytherapy was conducted 4 to 6 weeks after surgery, following external beam radiotherapy. Prior to brachytherapy, patients were on a 2-day diet without fiber and abundant meals, and they underwent enema the evening before the intracavitary application. High-dose-rate brachytherapy was performed by a remote after loading technique using vaginal applicator. The therapeutic dose ranged from 6–7 Gy per intracavitary application, 3 to 5 fractions in total, pursuant to the 2012 Clinical Center Kragujevac treatment protocol. The dose calculation was done according to the International Commissioning on Radiation Units (Report No. 38). The dose was calculated to 0.5 cm from the applicator surface. Bladder and rectal doses were determined at the points obtained by radiography, with contrast placed in the bladder and rectum.
A statistical analysis was performed using SPSS 20.0. The statistical significance was determined by Student t test, χ2 test, and, where appropriate, using Mann-Whitney U test. In addition, the Kaplan-Meier's method was used for OS. The statistical significance was assumed at P < 0.05.
| » Results|| |
Basic characteristics of the patients are shown in [Table 1], whereas the radiotherapy modalities, such as dose and number of fractions, are shown in [Table 3]. As many as 97.5% of all patients were older than age 65 years, with residence in urban area (in 63.8% of cases). The habit analysis showed that 17.5% of patients occasionally used alcohol, whereas 33.8% were smokers. In the patients' family history [Table 1], the most common hereditary diseases were malignancies, accounting for 40% of all morbidities, followed by cardiovascular diseases (22.5%). Comorbidities are also shown in the [Table 1]. Some 15% of patients had no comorbidities, with the most common comorbidities being hypertension (36.3%), diabetes mellitus (22.6%), and gallstones (12.5%). Most patients had either one or two deliveries, whereas over 80% had no abortions or one abortion in their lifetime. The most common histopathological type of cancer was endometrial adenocarcinoma, in 90% of cases.
|Table 2: Patients groups depending on the risk of adjuvant radiotherapy (ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer) according to FIGO stages|
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We analyzed the effects of postoperative radiotherapy during the five-year period, as overall survival, disease PFS or fatal outcome. The median follow-up time for all patients was 52 months (range, 13–64). OS for a 5-year period was 80%, whereas the median OS was 41, 5 months (range, 1–60). As many as 66.3% of patients were progression-free during this period. The median disease-free survival was 21.5 months (range, 1–59). Fatal outcomes occurred in 20% of patients (7% died due to endometrial carcinoma, 13% unrelated to the disease in question).
The patients who underwent adjuvant radiotherapy were divided into risk groups according to the ESMO-ESGO-ESTRO Consensus Conference recommendation, and the results showed the shortest survival in the high-risk group of patients [Figure 1]. The highest risk group was least represented because more than 65% of patients were in the FIGO I stage of disease. Patients groups from the risk of adjuvant radiotherapy (ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer) according to FIGO stages [Table 2].
|Figure 1: Five-year survival and progression-free survival. (a) Overall survival, (b) Progression-free survival, (c) Overall survival according to the risk groups for the adjuvant radiotherapy, and (d) Progression-free survival according to the risk groups for the adjuvant radiotherapy|
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As shown in [Table 3], most patients were treated with 45 Gy, whereas in 70% of the patients high-dose-rate (HDR) brachytherapy per-fraction dose was 7 Gy. In 76.3% of patients, combined postoperative external beam radiation and intracavitary brachytherapy were performed. There were no complications in 72.5%. The most common symptoms caused by late irradiation toxicity arose from the gastrointestinal tract. Toxicity was usually moderate [Table 4]. Five-year survival depended on site of cancer recurrence.
As shown in [Figure 2] and [Figure 3], the influence of different parameters on the five-year survival was examined. The following variables were analyzed: FIGO stage of the disease, histopathological type of tumor, application of postoperative radiotherapy, organ site of late toxicity and grading toxicity, localization of the metastases occurrence, comorbidities but also age, smoking, alcohol consumption, number of deliveries and abortions [Figure 2] and [Figure 3]. The statistically significant values were shown for comorbidities (P = 0.033*), FIGO stage (P = 0.000*), localization of metastases (P = 0.039*), postoperative radiotherapy (P = 0.031*), and late toxicity organ site (P = 0.013*).
|Figure 2: Influence of the different factors on the overall survival. (a) Age, (b) Residence, (c) Alcohol use, (d) Number of deliveries, (e) FIGO stage, and (f) Histological type of tumor|
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|Figure 3: Overall survival according to radiotherapy modalities and grade of toxicity and distribution of late toxicity according to risk groups. (a) Overall survival according to radiotherapy modalities, (b) Overall survival according to grades of the late radiation toxicity, (c) Distribution of organ localization of late radiation toxicity according to risk groups, and (d) Overall survival according to localization of distant metastases|
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| » Discussion|| |
The study objective was to identify the factors that may influence the 5-year survival and disease-free survival, and analyze postoperative radiotherapy efficiency and treatment parameters that can affect endometrial cancer patients' outcome when divided into four risk groups.
Five-year survival was 80%, and disease-free survival rate was 66.3%. Fatal outcome happened in 20% of observed cases because of disease progression (7%) or unrelated comorbidities (13%). Simultaneously, liver and bone metastases were found in 2.5% of patients, whereas 1.3% had bone metastases, 3.8% liver metastases, 2.6% lung metastases, and bone metastases with para-aortic lymph node metastases were found in 3.8% of patients [Table 1]. In a similar study, Mezouri et al. found comparable results. A study by Jabson et al. showed that in patients with adnexal involvement during the 5-year period, 2.2% of cases had local or regional recurrence, and 26.2% developed distant metastases.
We found that long-term prognosis and patients' OS were not influenced by socio-demographic differences, patients' habits, number of deliveries, abortions, pathophysiological type of tumor, or grade of toxicity [Figure 2] and [Figure 3]. Comorbidities (P =0.033*), FIGO stage (P = 0.000*), metastases localization (P = 0.039*), adjuvant radiotherapy (P = 0.031*), and late toxicity organ site (P = 0.013*) had significant influence on time to progression [Figure 2] and [Figure 3].
On the contrary, a study conducted by Fader et al. showed that socio-economic, geographical, and factors associated with a lack of life benefits were associated with advanced disease, lack of adequate care, and shorter survival. Furthermore, they proved that African and American women with the diagnosis of endometrial cancer had significantly shorter OS, indicating necessity to standardize treatment methods for endometrial cancer, and that treatment in large centers gave better results. Choi et al. had conducted a study that involved 139 patients with endometrial cancer, FIGO stages I-III, treated with adjuvant radiotherapy. Contrary to our study, their patients' 5-year survival and disease-free survival rates were 58.7% and 59.2%, respectively. They showed that stage of disease, type of surgical intervention, and histological type of tumor significantly affected disease prognosis and long-term survival. In addition, Irwin et al. confirmed that predictors of shorter disease-free survival were high FIGO stage, involvement of the lower uterine segment, and age. Inan et al. showed that FIGO stage Ia patients belong to a low-risk group for adjuvant radiotherapy treatment. Their patients' 5-year survival of more than 90% could be attributed to the lower FIGO stages. Donnelly et al. conducted a retrospective study depending on the analysis of bladder dosimetric parameters, for patients with endometrial cancer treated with HDR brachytherapy. The total survival of their patients was 89%, similar to our results.
In our patients, toxicity was usually mild to moderate, from grade 2 to 4, whereas grade 5 was not recorded [Table 4]. Grade 1 radiotherapy toxicity was not recorded. It should be noted that the patients with low-grade toxicity may have ignored their symptoms. The literature describes that oncology patients are less likely to report their mild and moderate symptoms to their doctors. Similarly, Hernández-Moreno's study, from the analysis of radiotherapy effects in patients with pelvic radiotherapy, showed that the majority of patients experienced mild toxicity of grade 1 or 2. Roszak et al. found that in adjuvant radiotherapy late toxicity appears in 16.3% of cases.
Limitations of our study were that the study was conducted in a single center and on a small sample of patients. In addition, majority of patients were older than 65 years.
Our study confirmed that adjuvant radiotherapy treatment is safe and efficient method, with the usual 5-year survival rate and an acceptable level of toxicity. We showed that the risk of disease recurrence can be predicted with patient classification into appropriate risk groups for the adjuvant radiotherapy administration [Figure 1].
Adjuvant radiotherapy can potentially prolong the survival and prevent the recurrence with acceptable level of toxicity to preserve patients' quality of life. Patient classification into appropriate risk groups, from the ESMO-ESGO-ESTRO Consensus Conference recommendation for adjuvant therapy, provides possibility for individualization of adjuvant treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]