**3. The role of adjuvant radiation therapy in management of endometrial cancer**

The role of radiation therapy in management of endometrial cancer is still under investigation with inconsistent findings and there are no solid conclusions. Improvement in disease-free survival rates is noted only.

## **3.1. Pelvic external beam radiation therapy (EBRT)**

was carried out with mitomycin C and cisplatin. Intraoperative and postoperative adverse events were uneventful. Two patients developed early recurrences at 2 and 10 months and both died afterwards. The remaining three patients were alive and disease-free at 7, 23 and 39

Abu-Zaid and colleagues [51] studied the combination of cytoreduction and HIPEC in 2 and 4 patients with primary advanced and recurrent endometrial cancer, respectively. Optimal cytoreduction was achieved in 5 patients. HIPEC was carried out with doxorubicin and cisplatin. Intraoperative and postoperative adverse events were uneventful. All patients received adjuvant chemotherapy (carboplatin and paclitaxel). Despite optimal debulking, one patient with an aggressive histology (clear cell carcinoma) relapsed within 6 months and died 5 months later because of metastatic spread to liver and pelvis. One patient with suboptimal cytoreduction (more than 2 cm residual disease) developed liver recurrence within 3 months and was still alive with disease at a follow-up of 6 months. The remaining patients were alive

Another study done in France [52] included 13 patients treated with cytoreduction and HIPEC for management of endometrial cancer with peritoneal metastases. One patient was lost to follow-up. Following HIPEC, three patients died before the first year, and two patients approximately died at first year and first year and half, respectively. Three patients were alive with disease, and 4 patients were alive without disease, between approximately 2 and 125

In the above-mentioned studies, disease-free survival and overall survival rates were largely affected by degree of peritoneal cancer index, cytoreduction completeness and tumor pathol‐

Despite promising results, almost all the existing studies are limited by their retrospective study designs, lack of randomized controlled trials, short follow-up periods and small sample

The logic for using HIPEC is chiefly attributed to the straightforward temperature-improved cytotoxicity of the intraperitoneal chemotherapeutic agents [53, 54]. Moreover, HIPEC aims to deeply penetrate the residual microscopic deposits [53, 54]― the primary source of surgical failure and early recurrence rates [43, 51, 52, 55, 56] in recurrent endometrial cancer. Moreover, HIPEC avoids the needless chemotherapy-related systemic toxicities while maximizing the local concentrations [57]. The most frequently used HIPEC agents include cisplatin [58]

Generally, morbidity and mortality of cytoreduction and HIPEC are greatly influenced by the surgeons' expertise and learning curve [61]. A recent systematic review by Chua and collea‐ gues [62] demonstrated that the morbidity rate associated with cytoreduction and HIPEC

range from approximately 12% to 52%, whereas mortality rate range from 1% to 6%.

sizes. This is an interesting arena for research and further studies are needed.

and disease-free without recurrence at follow-up at 35, 34, 19, and 7 months.

months with fair performance status.

162 Contemporary Gynecologic Practice

months period.

ogy [43, 51, 52].

doxorubicin [59] and mitomycin C [60].

The efficacy of adjuvant external beam radiotherapy (EBRT) was studied in five randomized clinical trials [40, 41, 63-69]. Only ASTEC/EN.5 clinical trial included a substantial percentage of patients with aggressive serous or clear cell histology (6.5%) [64]. Conversely, in all the other remaining trials, endometrioid adenocarcinoma was the most predominant histology. All trials demonstrated advantages of EBRT in terms of loco-regional control (disease-free survival) only, but failed to yield any survival benefits. Furthermore, at a median follow-up of 21 years, an update of Oslo trial demonstrated that patients under 60 years of age who were administered adjuvant EBRT experienced lower overall survival rates and higher risks of harboring secondary malignancies, as high as 30% [69]. Moreover, in the PORTEC trial, patients who received EBRT had worse quality of life as opposed to the observation patients [68]. The EBRT toxicities commonly involved the urogenital and gastro-intestinal tract systems and included urinary leakage and urgency, in addition to frequent diarrheal attacks and stool incontinence. These findings were endorsed in two recently published meta-analyses [70, 71]. Subgroups analyses were completed and demonstrated that EBRT had improved disease-free survival in patients with high risk of recurrence (p=0.03), however, EBRT had harmful outcomes on overall survival in patients with low or intermediate risk of recurrence (p=0.03) [70]. Therefore, it can be concluded that adjuvant EBRT should be largely employed for management of high-risk patients with primary advanced or recurrent endometrial cancer. Moreover, long-term related toxicities of EBRT should be considered wisely when adjuvant EBRT is selected for younger patients. EBRT should be selected in patients with high-risk histological features, positive lymph nodes or primary advanced stage disease (III/IV) [28]. The suggested histopathological features for determining high-risk disease include: tumor grade 3 (poorly differentiated), more than 50% of myometrial invasion, lymphovascular space invasion, non-endometrioid histology (serous, clear cell, undifferentiated, small cell, anaplas‐ tic, etc), cervical stromal involvement, advanced stage disease (FIGO stage III and IV) and older age (more than 60 years) [28].
