|Ahead of print publication
Adjuvant radiotherapy for uterine carcinosarcoma: A retrospective assessment of treatment outcomes
Ugur Yilmaz1, Senem Alanyali2, Arif Bulent Aras2, Zeynep Ozsaran2
1 Department of Radiation Oncology, Diyarbakir Gazi Yasargil Education and Research Hospital, Diyarbakir, Turkey
2 Department of Radiation Oncology, Ege University Faculty of Medicine, Izmir, Turkey
Department of Radiation Oncology, Diyarbakir Gazi Yasargil Education and Research Hospital, Uckuyu Mah., Kayapinar, Diyarbakir 21010
Source of Support: None, Conflict of Interest: None
Objectives: The objective of the study is to understand the impact of adjuvant radiotherapy (RT) and prognostic factors for patients diagnosed with uterine carcinosarcoma.
Materials and Methods: The records of 31 patients receiving adjuvant RT between the dates of September 2003–January 2013 in our clinic were evaluated retrospectively. Surgery was performed in 27 (87%) patients as staging laparotomy, for 4 patients as total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pelvic external beam radiotherapy (EBRT) was 4500–5040 cGy in 25–28 fractions. In addition, 23 patients received brachytherapy following EBRT, 12 patients received adjuvant, and 1 patient received neoadjuvant chemotherapy (CT).
Results: The median age was 63 (between 30 and 78). The stage distribution of the patients was as follows: Stage I, 20 (64%); Stage II, 7 (23%), and Stage III, 4 (13%) patients. Five-year locoregional control (LRC) rate was 100%, disease-free survival (DFS) and overall survival (OS) rates were 65.5% and 66.2%, respectively. Stage I or II patients have a tendency for better 5-year OS and DFS rates than Stage III patients (73.1% vs. 42.9% and 72.7% vs. 42.9%; P = 0.065 and 0.051). Regarding lymph node dissection was performed or not, 5-year OS (64.7% vs. 75.0%) was not statistically different between groups (P = 0.77). Five-year OS and DFS rates were 69.2% and 61.5% for patients receiving CT (adjuvant or neoadjuvant) versus 63.7% and 68.8% for patients not receiving CT; P = 0.63 and P = 0.89, respectively. Based on the analysis of peritoneal washings, 5-year OS was 0% for patients with malignant or suspicious cytology whereas 89% for patients with benign cytology (P = 0.000). A negative correlation was observed between mitotic count of sarcomatous component and DFS time (rs = −0.812 and P = 0.05).
Conclusions: Surgery and adjuvant RT seem beneficial for excellent LRC rate. However, survival rates are low due to distant metastases. Thus, there is a great need for better systemic therapies.
Keywords: Radiotherapy, survival, uterine carcinosarcoma
|How to cite this URL:|
Yilmaz U, Alanyali S, Aras AB, Ozsaran Z. Adjuvant radiotherapy for uterine carcinosarcoma: A retrospective assessment of treatment outcomes. J Can Res Ther [Epub ahead of print] [cited 2019 Dec 7]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=263539
| > Introduction|| |
Uterine sarcoma is very rare kind of cancer with aggressive features. In 2016, there were 60,050 new patients with the diagnosis of uterine corpus cancer in the USA and uterine sarcomas accounted for 5%–6% of them., Uterine carcinosarcoma (UCS), composed of both epithelial and mesenchymal components, is the most frequently seen uterine mesenchymal tumor and it was known as a malignant mixed mesodermal tumor or malignant mixed Mullerian tumor formerly. The staging system is same for both UCS and uterine carcinoma in 2009 International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging System for endometrial cancer, according to the similar progressing features, chemotherapy (CT) sensitivities and outcomes of immunohistochemical studies. UCS has a worse prognosis than Grade 3 endometrial cancer on the basis of treatment outcomes. The 5-year survival rate for Stage III UCS is about 30% and 50% for Stage I UCS.,
The standard management is surgical staging consisting of total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), retroperitoneal lymph node dissection (RPLND), and collection of peritoneal washings along with resection of any gross intra-abdominal disease., Although some physicians prefer CT, it is unclear if the prognosis is improved with any form of adjuvant treatment for patients with surgically staged IA UCS.,,,, For patients with surgically staged IB to IV UCS, adjuvant CT is preferred.
Adjuvant radiotherapy (RT) decreases the risk of pelvic recurrence.,,,, For better local control rates, some physicians prefer vaginal brachytherapy following surgery. There is limited data for administration of combined CT and RT as a sandwich or sequentially following surgery.,,,
Thirty-one patients with the diagnosis of UCS receiving adjuvant RT were evaluated in our study.
| > Materials and Methods|| |
The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of Helsinki 1975, as revised in 2000.
The records of 31 patients receiving adjuvant RT between September 2003 and January 2013 in Ege University Faculty of Medicine, Department of Radiation Oncology were reviewed for patient age, diagnosis date, type of primary surgery, histopathological features, FIGO stage, treatment details, dates of progression and death, and site(s) of first recurrence. The new 2009 FIGO staging system for carcinoma of the endometrium, which is also recommended for UCS was used to update the patient's surgical-pathological stage of disease.
External beam radiotherapy (EBRT) 4500–5040 cGy in 25–28 fractions was delivered to the tumor bed and pelvic lymphatics with 6–18 MV linear accelerators. All patients received EBRT and addition of brachytherapy was left to the discretion of the physician. Follow-up evaluation was every 3 months for the first 2 years, then every 6 months with routine gynecological examination and Pap smear.
IBM SPSS Statistics 22.0 was used for statistical analysis. Survival was calculated using the Kaplan–Meier method and compared by the log-rank test. Spearman rank correlation was used to test the association between survival times and tumor-related factors. P ≤ 0.05 was considered statistically significant.
| > Results|| |
Patient characteristics and treatment
Clinical, therapeutic, and pathological variables for patients are described in [Table 1]. The median age of our patients was 63 (between 30 and 78) and 27 (87%) patients were postmenopausal. About 27 (87%) patients underwent TAH, BSO, RPLND, and collection of peritoneal washings and 4 (13%) patients underwent TAH and BSO. With respect to the evaluation of pathological features, median tumor size was 7 cm, myometrial invasion was <½ for 12 (39%), lymphovascular invasion (LVI) was positive for 14 (45%), lymph node metastasis (LNM) was positive for 2 (6%), peritoneal lavage was suspicious for 1 (3%), and positive for 3 (10%) patients. Moreover, only 6 patients were well described for mitotic count of sarcomatous component and the median mitotic count was 11/10 high-power field. The stage distribution of the patients was as follows: Stage I, 20 (64%); Stage II, 7 (23%); and Stage III, 4 (13%) patients.
|Table 1: Patient related clinical characteristics, pathological data, and summary of treatments|
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About 12 patients received adjuvant CT; 9 with Stage I–II disease and 3 with Stage III disease. One patient with Stage II disease received neoadjuvant CT. All patients received EBRT, and in addition to it, 23 patients underwent high-dose-rate brachytherapy following EBRT.
Acute gastrointestinal or genitourinary side effects due to the RT were seen as Grade 1 in 3 patients, Grade 2 in 4 patients, and Grade 3 in 2 patients. Chronic side effects were seen as Grade 1 in 2 patients and Grade 4 in 1 patient for the development of rectovaginal fistula. In addition, 5 patients had vaginal stenosis.
Disease relapse and survival
At the time of analysis, the median duration of follow-up for patients alive at last contact was 73 months. About 11 (35%) patients died during follow-up. There was not any locoregional recurrence after RT. A total of 12 (39%) patients had distant metastases (DM); 6 of them with lung metastases and 3 of them with liver metastases. Time to DM was not known for 1 patient. Five-year locoregional control (LRC) rate was 100%; disease-free survival (DFS) and overall survival (OS) were 65.5% and 66.2%, respectively [Figure 1]. Depending on the status of peritoneal washing; 5-year OS was 0% for patients with malignant or suspicious cytology and 88.9% for patients with benign cytology (P = 0.000) [Figure 2]. Stage I or II patients have tendency for better 5-year OS and DFS rates than Stage III patients with 73.1% and 72.7% versus 42.9% and 42.9%; P = 0.065 and P = 0.051, respectively. Five-year rates of OS were 64.7% for patients undergoing lymph node dissection versus 75.0% for patients without lymph node dissection and the difference was not statistically significant (P = 0.77). Five-year OS and DFS rates were 69.2% and 61.5% for patients receiving CT (adjuvant or neoadjuvant) versus 63.7% and 68.8% for patients not receiving CT; P = 0.63 and P = 0.89, respectively.
|Figure 1: Kaplan–Meier survival curve of overall survival and disease-free survival|
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|Figure 2: Kaplan–Meier survival curve of overall survival for patients performed peritoneal washing|
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Mitotic count of sarcomatous component was known for 6 patients. There was a negative correlation between mitotic count of sarcomatous component and DFS time (rs = −0.812 and P = 0.05). However, there was not any association between DFS time and stages of these patients (rs = −0.62 and P = 0.19). A trend was seen for negative correlation between mitotic count of sarcomatous component and OS and LRC times (rs = −0.75 and P = 0.08 for each).
Age, menopausal status, depth of myometrial invasion, tumor size, tumor grade, LVI, and LNM were analyzed for influence on survival and none was found as prognostic factor.
| > Discussion|| |
UCS is highly aggressive tumor containing both carcinoma and homologous or heterologous sarcomatosis components. Both carcinoma and sarcoma elements derive from the same stem cells; however, especially epithelial component is dominant in biological behavior. LVI, high release of vascular endothelial growth factor, and poor prognosis are more common in UCS compared to endometrial sarcoma with high-grade features.
Treatment decisions are mostly based on the retrospective studies due to the rarity of UCS and the optimal management is not well defined yet. The standard management of UCS limited to the abdomen is surgery for both staging and initial treatment. Surgical staging and invasion depth are the most important prognostic factors. LNM rates are 14%, even in very low aggressive types limited with polyp. An upward stage migration occurred in 20% of patients after lymphadenectomy. Lymphadenectomy is the most important part of treatment with benefits of complete staging, treatment decision, and survival advantage. Accordingly, Nemani et al. evaluated Stage I–III UCS patients in Surveillance, Epidemiology, and End Results (SEER) retrospective analysis, whether they had lymphadenectomy or not. Median survival was 29 months and 5-year survival rate was 49% in lymphadenectomy arm, whereas median survival was 23 months and 5-year survival rate was 34% in nonlymphadenectomy arm, P < 0.0001. A similar trial was conducted by Garg et al. and they observed that death risk was decreased by 33% for lymphadenectomy performed patients. Multivariate analysis in Korean Radiation Oncology Group 13–08 retrospective trial revealed significant correlation between pelvic lymphadenectomy and locoregional recurrence-free survival, distant metastasis-free survival, and DFS; P = 0.015, 0.019, and 0.003, respectively. In our study, staging laparatomy was performed in 27 patients, and only TAH + BSO was performed due to medical comorbidities in 4 patients. Any significant survival difference was not seen between the groups.
UCS is treated similarly such as uterine serous papillary and clear cell carcinoma according to the international guidelines. DM is more common than local recurrences for uterine sarcomas. Although adjuvant therapies do not seem to contribute to any OS benefit in prospective trials, they have some contributions for the DFS and local control. Treatment decisions should be based on both the probability of side effects and the fact that median disease-specific survival is 3 months for patients having only surgery, 15 months for patients having both surgery and RT, 14 months for patients having both surgery and CT, and 31 months for patients having all the treatment modalities including surgery, RT, and CT. Nonetheless, observation is enough for patients with Stage I disease if myometrial invasion does not exist. Carboplatin and paclitaxel combination is effective and tolerable in CT trials for patients having total resection., In our study, postoperative RT was performed for all patients. Besides, 12 patients received adjuvant CT and 1 patient received neoadjuvant CT. On the basis of these treatment approaches, there is not any locoregional recurrence, whereas DM developed in 12 (39%) patients. CT did not have impact on survival in our study population. It could be due to our small sample size or the inadequate effect of CT for UCS.
The role of adjuvant RT for uterine sarcoma was first described by Salazar et al. Then, a lot of small retrospective trials also evaluated adjuvant RT. Although local control rate was high, there was not any OS benefit in most of trials. After hysterectomy, Stage I–II patients diagnosed with uterine sarcoma (leiomyosarcoma and carcinosarcoma) were randomly assigned to receiving adjuvant doxorubicin or to no further treatment in randomized Phase III Gynecologic Oncology Group (GOG) 20 trial. Some of the patients received EBRT before randomization. There were not any DFS or OS difference between the arms, but pelvic recurrence rate was 10% for the patients receiving RT and 23% for those who did not (P = 0.028). GOG Protocol 150 was a randomized Phase III trial of whole-abdominal irradiation versus cisplatin-ifosfamide-mesna as postoperative treatment for Stages I–IV UCS. There was not any significant difference between two groups for recurrence rate and survival; however, there was a trend favoring the CT arm. Regarding Grade 2, 3, or 4 late effects, gastrointestinal events occurred more often among those treated with whole abdominal irradiation than CT. When Makker et al. aimed to determine the progression-free survival (PFS) and OS for patients who received either platinum-based CT with or without RT or only RT in their retrospective trial, they found better PFS and OS trend in CT with RT arm, so their study corroborated GOG 150 trial results. Decreased recurrence risk and longer time to develop DM were seen after adjuvant RT in the trial of 300 patients conducted by Callister et al.; however, there was not any difference in DM rates and OS. In EORTC-55874 trial, patients with Stage I–II uterine sarcomas were randomized to either adjuvant RT or observation after surgery. Of the 224 patients, 91 had carcinosarcoma. No difference in either OS or DFS was demonstrated, but there is a decreased local recurrence for the UCS patients receiving RT (24% vs. 47%). Clayton Smith et al. evaluated adjuvant RT for UCS patients in the SEER database. Of the 2461 women, 890 received adjuvant RT. Five-year rates of OS were 41.5% and 33.2% (P < 0.001) for women receiving RT compared to those who did not receive, respectively. Further analysis revealed that women with Stages I–III disease experienced a benefit in OS (P = 0.03), while women with Stage IV disease experienced benefit in both OS (P < 0.001) and uterine-specific survival (P = 0.004) in RT group. In one of the more recently published retrospective trial, adjuvant EBRT >50 Gy was defined as an independent prognostic factor for better LRC (P = 0.01), OS (P = 0.03), and cancer-specific survival (P = 0.02). In the other recent trial, there was a tendency with adjuvant RT for increasing the median OS (P = 0.08).
Adding brachytherapy following EBRT has not been clear yet. About 23 of 31 patients had both EBRT and brachytherapy, remaining 8 patients had only EBRT in our study, and there was not any locoregional recurrence during follow-up.
Tumor stage, mitotic count, and histological type were independent prognostic variables for survival in a retrospective study on 249 patients with uterine sarcoma. There were 25 patients recurred with the diagnosis of UCS and the location sites of recurrence were as follows: 40% pelvis, 40% DM, and 20% both pelvic recurrence and DM. Apart from tumor stage and LNM, cell type (homologous versus heterologous), grade of sarcomatous and epithelial component, mitotic count of sarcomatous component, depth of myometrial invasion, LVI, and peritoneal cytology were important prognostics for UCS. Five-year OS was 65% in our study. Based on the analyses of the peritoneal washings; 5 years OS was 0% for patients with malignant or suspicious cytology and 89% for patients with benign cytology (P = 0.000) [Figure 2]. Although there are few patients having malignant or suspicious cytology for peritoneal washing, the results can be still remarkably compatible. Stage I or II patients have tendency for better 5-year OS and DFS rate than Stage III patients (73.1% and 72.7% vs. 42.9% and 42.9%; P = 0.065 and 0.051). Only 6 out of 31 patients were well described for mitotic count of sarcomatous component; nevertheless, it could be interesting that mitotic count of sarcomatous component has a negative correlation with DFS time (rs = −0.812 and P = 0.05). The potential prognostic factors including age, menopausal status, depth of myometrial invasion, tumor size, tumor grade, LVI, and LNM were analyzed and nothing was found as significant.
Survival outcomes of different trials comprising Stage I–III UCS patients are shown in [Table 2]. Given the fact that survival outcomes in our data are better than the other trials' survival rates; however, it could be reasonable due to the small cohort size and 87% of patients' early-stage disease in our study.
|Table 2: Outcomes of the treatment for the patients having adjuvant radiotherapy or chemotherapy with the diagnosis of carcinosarcoma|
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Depending on the treatment techniques, the addition of brachytherapy and the prescribed dose level, genitourinary and gastrointestinal disorders are the most frequent early and late side effects related to RT. Grade 3–4 late side effects were announced 3%–5.5% of the patients performed only EBRT., In our study, acute side effects on the gastrointestinal or genitourinary tract were seen as Grade 1 in 3, Grade 2 in 4, and Grade 3 in 2 patients; chronic side effects were seen as Grade 1 in 2 patients and Grade 4 in 1 patient for the development of rectovaginal fistula. In addition, 5 patients had vaginal stenosis.
| > Conclusions|| |
Although surgery and adjuvant RT provides excellent LRC, DM remains the major cause of mortality. The use of better systemic therapies could tend to decrease metastasis and increase survival.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]