**3.1 Adjuvant vaginal brachytherapy as monotherapy**

As reported above, we know that pelvic EBRT reduces the recurrence; however, it leads to severe side effects compared to follow-up without treatment in endometrial cancer. Radiotherapy via the vaginal route was considered to be more proper as vaginal recurrences are seen most in post-operative endometrial cancer patients. Similarly, with pelvic EBRT, VB treatment was not shown to be effective on the overall survival. However, while the vaginal recurrence rate is 0–3.1% in VB, the pelvic recurrence rate is 0–4.1% [28–30]. These rates are similar with pelvic EBRT and related to the lower toxic effects.

In the randomized controlled PROTEC-2 study comparing the effectiveness of pelvic EBRT and VB treatment, all patients were H-I risk endometrial cancer patients who had undergone TAH + BSO, but not lymphadenectomy. The patients were allocated to three groups as the group that received 23 fractions 46 Gy as pelvic EBRT, the high dose rate (HDR) group that received 7 Gyx3 fractions and the low dose rate (LDR) group that received 30 Gy VB. While the 5-year vaginal recurrence

was 1.8% with VB, it was 1.6% in the pelvic EBRT group (p = 0.74). The pelvic recurrence rate was higher in the VB group (3.8% vs. 0.5%, p = 0.02). However, the gastrointestinal side effects were significantly lower in the VB group compared to the EBRT group [30].

### **3.2 Adjuvant vaginal brachytherapy as boost**

A better loco-regional control can be achieved by adding VB to pelvic EBRT and the rate of vaginal recurrence would be seen as 0–2.7% and the rate of pelvic recurrence as 0.3–4.0% [29, 31–33]. Despite the absence of EBRT+/-VB randomized controlled study, boost VB may be added in the treatment of high risk patients whose vaginal recurrence is high and who receive low dose EBRT (45 Gy at 1.8 Gy/ fractions). There are randomized controlled studies comparing EBRT + boost VB and VB alone. In one of these studies, while the total pelvic recurrence rate was 0.4% in EBRT + boost VB group, it was 5.3% in the VB only group (p = 0.013). No difference was found between the groups with regard to vaginal recurrence and overall survival; however, the radiation toxicity was lower in the VB group [33]. In the studies of RTOG, applying 5–6 Gy VB boost only onto the vaginal surface as 45 Gy EBRTx3 fractions or 50.4 Gy EBRTx2 fractions is recommended [34, 35].

### **3.3 Vaginal brachytherapy and chemotherapy**

The effect of adding chemotherapy (CT) to VB was investigated particularly in high risk endometrial cancer patients who had the likelihood of distant metastasis. In a study conducted by Landrum et al., the 2-year progression-free survival was 91% in 23 patients including H-I risk early stage endometrial cancer, uterine serous carcinoma (USC) and clear cell carcinoma (CCC). Vaginal recurrence occurred in one patient (4.2%); this patient also had distant metastasis [36]. The effect of VB + CT was investigated in the GOG 249 randomized controlled study. In that study, while one group received EBRT, another group received VB + CT (3 cycles of carboplatin and paclitaxel). The study included the GOG 99 H-I risk patients, patients with stromal invasion and stage 1–2 USC and CCC. While the overall survival was 92% in the EBRT group, it was 92% in the VB + CT group at the end of the 2-year follow-up (p = NS). There was no significant difference between the vaginal recurrence rates in the two groups. While hematologic toxicity, neuropathy and fatigue were more common in the VB + CT arm, grade 2 diarrhea was more common in the EBRT arm [37].
