RADIATION THERAPY IN MANAGEMENT OF ENDOMETRIAL CARCINOMA: THE RESULTS OF A SINGLE INSTITUTION

F. Kouhen, M. Afif and N. Benjaafar 1. Mohammed VI University of Health Sciences (UM6SS). Casablanca, Morocco. Department of Radiotherapy, International University Hospital Sheikh Khalifa. 2. Mohammed V University In Rabat, Morocco.Department of Radiotherapy, NationalInstitute of Oncology. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 22 December 2019 Final Accepted: 25 January 2020 Published: February 2020


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Surgery is the primary treatment for endometrial cancer. The treatment following surgical staging is based on the risk of relapse and persistent disease, which is defined by the cancer stage at diagnosis and presence of prognostic factors.
Adjuvant radiotherapy options include pelvic radiation, vaginal brachytherapy or whole-abdomen radiation. Radiotherapy improves local control, but does not improve cancer specific or overall survival [4]. Radiotherapy alone has also curative potential in medically inoperable patients.
The aim of our retrospective study was to evaluate the results of adjuvant radiotherapy in management of endometrial carcinoma for Moroccan patients, and to retrieve prognostic factors influencing outcomes.

Materials and Methods:
A population-based registry encompasses patient's data from the north and the centre areas of Morocco. Between January 2011 and December 2012, 50 patients newly diagnosed with endometrial carcinoma has benefited from radiation therapy were retrieved. All patients were treated by conformational 3D radiotherapy.
Staging was made according to the 2009 International Federation of Gynecology and Obstetrics [FIGO].
Patients receiving external beam radiotherapy (EBRT) were treated using a four-field box technique (anteriorposterior and two laterals).
For patients receiving high dose rate (HDR) brachytherapy, a Nucletron HDR unit with Iridium-192 as the source wasused to prescribe the dose to 0.5 cm depth.A vaginal cylinder was used for most patients.
HDR brachytherapy fractional dose was converted to equivalent 2-Gy fractions assuming an a/b of 10 for tumor and 3 for normal tissue For each patient, we retrospectively collected information about symptoms, work-up, staging, and finely clinical outcomes (overall survival (OS), local control (LC)).
Toxicities were retrospectively assessed based on the Common Terminology Criteria for Adverse Events v4.0.
All Patients were examined at 3-month intervals for the first 2 years after treatment, then at 6-month intervals for the next 3 years, then yearly afterward Statistical analysis was performed using SPSS software, version 10.0. Local control and patient's survival distribution was calculated using the Kaplan-Meier method. Time to recurrence was calculated from the completion of radiation treatment to the time of histological or radiographicconfirmation of recurrence. The significance of the survival was tested by log-rank test. Multivariate analysis was performed using the Cox proportional hazard regression. A value of p less than 0.05 was considered statistically significant.

Results:
Median age of patients was 58 years (54, 5-56, 5) (Table 1). More than half of patients were post-menopausal (78%).Nineteen patients had risk factors such as arterial hypertension and diabetes and only one patient had history of taking tamoxifen for breast cancer.
The mean size was 2, 9 cm (1, 3-6,7cm). Seventy-eight percent of the patients had an abdomino-pelvic CT scan to evaluate the loco regional extent and 22 % of them had a pelvic magnetic resonance imaging (MRI) along with abdominal CT. All of our patients had a chest X-ray for evaluation of thoracic metastases.

Treatment modalities (Table 2):
For the external beam radiotherapy (EBRT), all patients were treated by conformational 3D radiotherapy using a four-field box technique (anterior-posterior and two laterals).
The clinical target volume (CTV) included the proximal vagina, the parametrial tissues, and the internal, external and distal common iliac lymph node regions up to the upper S1 level. If the external or internal iliac lymph node are involvement, the common iliac lymph node regions are to be included up to the aortic bifurcation with Planning Target Volume consists of the CTV with a 7-10 mm margin a dose range of 45 to 50.4 Gy at 1.8 Gy fractions.
Vaginal cuff brachytherapy was delivered in 65% of patients at a dose of 10 Gy, two fractions of five Gy was be specified at 5 mm from the surface of the cylinder, in the central plane. Proximal one -third of vagina were irradiated.
The mean of total treatment duration was 50 days.
All patients were completed the radiotherapy without any interruptions. Main acute toxicity was diarrhea (66% of patients: 40% were grade 1 and 26% were grade 2.) and radio cystitis (28% of patients: 12%were grade 1 and 16% were grade 2) and no grade 3 or 4 was noted.
1296 Table 2: Therapeutic modalities   Modalities  FIGO stage  I  II  IIIA  IIIB  IIIC  LOW  INTERMEDIATE  HIGH Surgery + Concomitant radiochemotherapy Qualitative variables presented as number and percentages n (%) Three patients had local recurrence, one patient developed distant metastases.
The overall 5-year survival rate for our study was 90,1 %, and the overall local control rate was 69,6 % ( Figure 2). A univariate and multivariate analysis was achieved to define prognostic factors associated to recurrences (Table 4).
In univariate analysis, old age and lymph-vascular space invasion were significantly associated with local recurrence. The involvement of old age was confirmed in multivariate analysis.
We could not demonstrate the role of FIGO stage, histologic type and tumor grade as prognostic factors involved in relapse because of the small number of events. 1297

Discussion:
Endometrial carcinoma is the most common gynecologic malignancy in developed countries and the second most common in developing countries [1].
Most cases of endometrial cancer occur between the ages of 60 and 70. A few cases may occur before age 40, which is consistent with our results with a median age of 58 years.
The foremost symptom was, similar to the reports in the literatures reviewed, abnormal perimenopausal or postmenopausal vaginal bleeding [5].
The majority of cases are diagnosed at an early stage [3]. In our series, 70, 4% of cases are diagnosed at FIGO stageI.
Endometrial cancer can be organized broadly into two categories: type I, or endometrioid adenocarcinoma, is the most common histologic type of endometrial cancer which accounts for more than 80% of cases [6], and type II is characterized by clear cell and papillary serous tumor histologies.
Multiple prognostic factors exist for endometrial cancer. These prognostic factors generally are related to surgical pathologic findings. As in all cancers, the stage of the disease is the most important prognostic factor [7], [8].
In addition to stage, other pathologic factors are used to determine risk of recurrent or persistent disease: histopathologic subtypes, the degree of histologic differentiation of endometrial cancer, the degree of myometrial invasion, presence of lymphovascular invasion within the cancer, tumor size, peritoneal cytology, lymph node metastasis, older age, expression of the cell adhesion molecule L1CAM. In our series, stage, age, histological type, grade, depth of myometrial invasion, and presence of lymph-vascular space invasion are prognostic factors significantly associated with local recurrence [9].
In this regard, the European Society for Medical Oncology (ESMO), subdivides stage I into three risk categories : low, intermediate, or high-risk for recurrence [10].
The gold standard management of endometrial cancer is surgery, consisting of a total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic and paraaortic lymph node dissection [11].
The site of first relapse is usually the upper vagina, or vaginal vault, and this can be reduced by adjuvant postoperative radiotherapy [12].
The risk of relapse after surgery for low-risk and low-intermediate risk disease is very low. Generally, no further treatment isrecommended.
After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. Recent data suggested that VBT is as effective as EBRT but less toxic and therefore considered as standard of care in patients with a certain risk of local recurrence [17]. The randomized PORTEC 2 trial estimated that 5-year rates of vaginal recurrence were 1.8% (95% CI 0.6-5.9) for VBT and 1.6% (0.5-4.9) for EBRT. 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% (2.8-9.6) for V cuff BT and 2.1% (0.8-5.8) for EBRT. Rates of acute grade 1-2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12.6%vs 53.8%).
Sorbe 2011 reported a significant difference in locoregional relapse in favour of the EBRT plus Vaginal brachytherapy group for women with endometrial carcinoma of intermediate-risk but significantly more severe late side effects [18].

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Vaginal cuff Brachytherapy alone may be also sufficient for Stage II disease presenting in the absence of other highrisk features [22].
For stage III disease, chemotherapy was often recommended as a single-modality treatment due to increased risk for relapse with an increasing number of extrauterine sites of disease.
However, multiple studies suggest the benefit of the combination of chemotherapy and external radiotherapy in order to reduce the risk of both local and distant recurrence [23], [24], [25].
A number of trials are currently ongoing which further explore the role of concurrent chemoradiation and/or adjuvant chemotherapy for patients with high-risk EC.
The RTOG have reported a phase II trial of concurrent pelvic radiotherapy (45 Gy in 1.8 Gy fractions and a brachytherapy boost) and cisplatin (2 courses of 50 mg/m2 on days 1 and 28), followed by four courses of cisplatin and paclitaxel after RT for high risk or advanced stage endometrial carcinoma [26]. At 4 years pelvic, regional and distant recurrence rates are 2% and 19%, respectively. Overall survival and disease-free survival (DFS) rates at 4 years are 85% and 81%, respectively with excellent treatment completion rate and expected toxicity.
Two ongoing randomized trials comparing concurrent chemoradiation and adjuvant chemotherapy (two cycles of cisplatin during RT, followed by four adjuvant cycles of carboplatin and paclitaxel), with pelvic radiation alone in high risk and advanced stage endometrial carcinoma: PORTEC-3(Phase III trial) and GOG-258(phase II trial).
The American Society for Radiation Oncology (ASTRO) guideline recommend that for women with grade 1 or 2 cancer and less than 50% myometrial invasion or grade 3 cancer and less than 50% myometrial invasion, the vaginal brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence and is preferred. Patients with grade 3 cancer and less than 50% myometrial invasion or cervical stroma invasion may benefit from pelvic radiation to prevent pelvic recurrence. For women with high-risk early-stage disease and advanced disease, chemotherapyis recommended (with or without radiation therapy) [27].
3D-conformal radiotherapy typically employs four photon fields (AP/PA and opposed laterals) [28] inducing irradiation of large volumes of small bowel, rectum, bladder and femoral heads that can increase the risks of acute and late toxicity.
In our study, all patients were treated by conformational 3D radiotherapyand it was generally tolerated. The most commun late toxicities are represented by gastrointestinal and urinary toxicities [33].
Our results are comparable to data published in international studies, with an overall 5-year survival rate for our study of 90,1 %, and an overall local control rate of 69,6 %. Most relapses were associated with locally advanced disease.

Conclusion:
In Our country, endometrial carcinoma is a common cancer, with mostly diagnosed at early stage. The results of our study confirm that radiation therapy is a good option for treatment of endometrial carcinoma, and it is associated to good outcomes with an overall 5-year survival rate of 90,1 %, and an overall local control rate of 69,6 % with age and lymph-vascular space invasion as prognostic factors of relapse. The IMRT shows great promise in the treatment of endometrial carcinoma to reduce the rate of both acute and late side effects.

Conflict of interest:
"The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper."