**4. The role of adjuvant chemotherapy in management of endometrial cancer**

The role of adjuvant chemotherapy has been studied in patients with early-stage intermediateto-high risk endometrial cancer, as well as patients with primary advanced, inoperable or recurrent late-stage endometrial cancer [39, 75-81]. The efficacy of postoperative chemotherapy was studied in a total of nine randomized clinical trials [39, 75-81]. The following trials included a substantial percentage of patients with the aggressive serous or clear cell histology: NSGO-EORTC (37%), GOG122 (25%), GOG184 (18%) [39, 78, 81]; the vast majority of patients had endometrioid adenocarcinoma histology.

Three clinical trials compared chemotherapy schedules with radiotherapy [39, 75, 76]. Two randomized clinical trials compared between one group of patients receiving cyclophospha‐ mide–doxorubicin–cisplatin, and one group of patients receiving pelvic EBRT. There were no benefits between both groups with respect to 5-year progression-free survival and overall survival rates [75, 76]. Conversely, GOG122 trial demonstrated statistically significant 5-year progression-free survival (50% and 38%, respectively; p=0.007) and overall survival (55% and 42%, respectively; p=0.004) rates between one group of patients receiving doxorubicin– cisplatin, and one group of patients receiving EBRT. All patients studied in COG122 study had advanced stage disease (III/IV) with less than 2 cm residual disease post-surgery [39].

Four clinical trials explored the advantage of adding a chemotherapy regimen to EBRT [77-79]. Three clinical trials (MaNGO ILIADE-III, Kuoppala and GOG34) demonstrated no progres‐ sion-free survival or overall survival benefits of combined treatment (chemotherapy plus radiotherapy) versus EBRT alone. However, the NSGO-EORTC trial showed that postopera‐ tive chemotherapy was correlated with an improved 5-year progression-free survival rate (79% and 72%; p=0.004), but not overall survival benefits [77]. There are discrepancies for the reported results among studies and these can be attributed to the variances of treatment methods such as: percentage of patients with advanced stage disease (stage III–IV) and choice of chemotherapy regimens. Therefore, such studies must be interpreted with caution.

loco-regional control (less than 2% at 5-year period for both arms), disease-free survival and overall survival [63, 73]. Vaginal brachytherapy is associated with considerably fewer gastrointestinal tract toxicities (less diarrheal attacks and stool incontinence) and a better functioning social quality of life [72-74]. Sorbe and colleagues [63] compared combination of EBRT and brachytherapy versus brachytherapy alone: there was no 5-year overall survival benefit (89% and 90%, respectively; p=0.548). However, the 5-year pelvic and loco-regional recurrences were much more common in the vaginal brachytherapy alone group (1.5% and 5%, respec‐ tively; p=0.013). It was concluded that combined radiation therapy (EBRT and vaginal brachytherapy) should possibly be reserved for high-risk patients, whereas vaginal brachy‐

In conclusion, vaginal brachytherapy, to a certain degree, effectively decreases the risk of vaginal recurrence in patients with risk factors while minimizing the radiation-related toxicities. In patients with early-stage endometrial cancer, vaginal brachytherapy should the

**4. The role of adjuvant chemotherapy in management of endometrial**

The role of adjuvant chemotherapy has been studied in patients with early-stage intermediateto-high risk endometrial cancer, as well as patients with primary advanced, inoperable or recurrent late-stage endometrial cancer [39, 75-81]. The efficacy of postoperative chemotherapy was studied in a total of nine randomized clinical trials [39, 75-81]. The following trials included a substantial percentage of patients with the aggressive serous or clear cell histology: NSGO-EORTC (37%), GOG122 (25%), GOG184 (18%) [39, 78, 81]; the vast majority of patients had

Three clinical trials compared chemotherapy schedules with radiotherapy [39, 75, 76]. Two randomized clinical trials compared between one group of patients receiving cyclophospha‐ mide–doxorubicin–cisplatin, and one group of patients receiving pelvic EBRT. There were no benefits between both groups with respect to 5-year progression-free survival and overall survival rates [75, 76]. Conversely, GOG122 trial demonstrated statistically significant 5-year progression-free survival (50% and 38%, respectively; p=0.007) and overall survival (55% and 42%, respectively; p=0.004) rates between one group of patients receiving doxorubicin– cisplatin, and one group of patients receiving EBRT. All patients studied in COG122 study had

advanced stage disease (III/IV) with less than 2 cm residual disease post-surgery [39].

Four clinical trials explored the advantage of adding a chemotherapy regimen to EBRT [77-79]. Three clinical trials (MaNGO ILIADE-III, Kuoppala and GOG34) demonstrated no progres‐ sion-free survival or overall survival benefits of combined treatment (chemotherapy plus radiotherapy) versus EBRT alone. However, the NSGO-EORTC trial showed that postopera‐ tive chemotherapy was correlated with an improved 5-year progression-free survival rate (79% and 72%; p=0.004), but not overall survival benefits [77]. There are discrepancies for the reported results among studies and these can be attributed to the variances of treatment

therapy alone should be reserved for purely medium-risk patients.

adjuvant treatment of choice over EBRT.

164 Contemporary Gynecologic Practice

endometrioid adenocarcinoma histology.

**cancer**

However, overall, a recently published meta-analysis covering a total of nine clinical trials showed that adjuvant chemotherapy was correlated with a statistically significant overall survival benefit (HR=0.74 [95% CI: 0.62–0.89]; p=0.0009), associating with an absolute differ‐ ence of 3% in 5-year survival rate [80].

Two clinical trials endeavored to compare chemotherapy regimens and the superiority of either of them in terms of progression-free survival or overall survival rates failed to take place [81, 82]. Fujimura and colleagues [81] considered one group of patients with cyclophospha‐ mide–doxorubicin–cisplatin, and one group of patients with etoposide–cisplatin. Homesley and colleagues (the GOG184 trial) [82] considered one group of patients for doxorubicin– cisplatin–placitaxel, and one group of patients for doxorubicin–cisplatin. In this study, the addition of paclitaxel to a cisplatin–doxorubicin regimen was accompanied with substantial chemotherapy-related side effects, mainly neurologic and hematologic [82].

There is an ongoing randomized clinical trial GOG209 phase III (paclitaxel–carboplatin versus paclitaxel–doxorubicin–cisplatin for management of recurrent/advanced endometrial cancer) [83]. Preliminary findings demonstrated that carboplatin–placitaxel combination was not inferior to doxorubicin–cisplatin–placitaxel with respect to progression-free survival (compa‐ rable median of 13-14 months; p >0.05) and overall survival (32 versus 38 months, respectively; no statistical significant difference: p >0.05) and was associated with reduced toxicity: periph‐ eral neuropathic toxicity grade 2 or higher (19% versus 26%), thrombocytopenia (12% versus 23%), metabolic imbalances (8% versus 14%), vomiting (4% versus 7%) and diarrhea (2% versus 6%) [10]. However, in consideration of the paclitaxel–doxorubicin–cisplatin associated toxicity, the combination of paclitaxel–carboplatin probably stands as the most preferred utilized chemotherapy regimen, and its administration is supported by the GOG209 trial above [83] and many other retrospective studies [51]. More studies are needed.

Previous studies have demonstrated that neoadjuvant chemotherapy with subsequent optimal cytoreduction for patients presenting with primary advanced endometrial cancer yielded no residual disease in 79% to 100% of all patients treated [84, 85]. Additional studies are needed.
