**4. Vaginal brachytherapy treatment in high-risk histology**

More aggressive treatments are used in uterine serous cancer (USC), clear cell carcinoma (CCC) and carcino-sarcoma (CS), which are the high risk histologies of endometrial cancer [38]. Most of the large studies including PORTEC-1, GOG 99 and PORTEC-2 [6, 8, 30] included early stage endometrial cancer patients and not high-risk patients. However, in the GOG 249 study, 20% of the patients were USC and CCC patients [37]. In a study conducted by Creasman et al., the outcomes of stage 1 high risk patients were found to be similar to those of grade 3 endometrioid type adeno-carcinoma patients [39]. Despite the presence of vaginal recurrence at a rate of 0–2.7% in stage 1–2 patients with high risk histology, the pelvic recurrence rate was found to be 0–9% [40–43]. In a study investigating USC patients, while the 5-year survival rate was 94% in patients who received VB + CT, it was 65% in patients who received LDR + EBRT but not CT [40]. In another study, USC patients

**161**

*Brachytherapy in Endometrial Cancer*

*DOI: http://dx.doi.org/10.5772/intechopen.92703*

CT did not have a great contribution [42, 43].

through advancements in radiology.

medically inoperable patients (**Table 3**) [50].

*4.1.1 Patient characteristics*

received VB + CT (six cycles of carboplatin and paclitaxel) and the vaginal, pelvic and distant metastasis rates were found to be 0, 9, and 10%, respectively, and the 5-year survival rate was 90% [41]. The effectiveness of VB alone was investigated in endometrial cancer patients with high risk histology. Some authors reported that

**4.1 Brachytherapy for treatment of medically inoperable endometrial cancer**

Medically inoperable endometrial cancer patients should be meticulously evaluated pre-operatively by a gynecologic oncologist. Most of these patients have cardiac diseases, pulmonary diseases, hypertension, diabetes mellitus, cerebro-vascular disease, renal disease, syndromes such as Marfan syndrome, advanced age and other malignancies. Morbid obesity is a relative contra-indication for the operation depending on the experience of the surgeon and the condition of the patient. Clinical performance of the patients is of vital importance as a pre-operative parameter. All of these patients should be evaluated pre-operatively for local or general anesthesia by experienced anesthetists. The hormone therapy (progestin, aromatase inhibitors) option is also available besides the radiotherapy option for clinical stage 1, grade 1 patients who are not eligible for surgery, for patients with endometrioid type endometrial cancer, for those below the age of 40 years and those willing to have a child [46]. Regression has been detected in 55% of the patients treated in this way [47]. Levonorgestrel-releasing intra-uterine devices (LNGIUDs) may be added to treatment of patients who have precancerous and stage 1, grade 1 endometrioid type endometrial cancer [48]. The patients are meticulously evaluated with CT or MRI with regard to tumor diameter, myometrial invasion depth, cervical involvement, ovarian involvement and pelvic para-aortic lymph node involvement if hormone therapy is planned, as oral regimens have the likelihood of recurrence at a rate of 25% despite the 50% or above success rates [49]. While endometrial cancer staging is done surgically according to the recent International Federation of Gynecology and Obstetrics (FIGO) 2009 classification, clinical staging is used in

The patients should be meticulously evaluated for pelvic examination and distant metastasis if clinical staging would be used. Vagina, cervix and the uterus are evaluated, presence of a mass lesion is examined and the search for parametrium involvement is attempted through bimanual (rectal-vaginal) examination. Computed tomographies of the thorax, abdomen and the pelvis are performed for distant metastasis and MRI is used for assessment of the uterus and the pelvis as the negative predictive value is >85% for myometrial invasion in contrast-enhanced T2-weighted

As mentioned above, the standard treatment of endometrial cancer is TAH + BSO (total abdominal hysterectomy + bilateral salphingo-oopherectomy) and lymphadenectomy when indicated, however, this standard treatment cannot be performed in a group of patients due to their medical disorders and clinical performances. In these patients, definitive radiotherapy is applied for clinical stage 1 patients, neo-adjuvant therapy is applied to patients with local advanced stage disease and brachytherapy alone or radiotherapy with addition of EBRT is applied as palliative treatment in patients who have complaints such as bleeding and pelvic pain. While LDR VB+/−EBRT has been used recently in the treatment of these patients, HDR VB+/−EBRT is widely used today [44, 45]. The treatment of medically inoperable endometrial cancer patients is planned better and more effectively

#### *Brachytherapy in Endometrial Cancer DOI: http://dx.doi.org/10.5772/intechopen.92703*

*Translational Research in Cancer*

the EBRT group [30].

**3.2 Adjuvant vaginal brachytherapy as boost**

**3.3 Vaginal brachytherapy and chemotherapy**

common in the EBRT arm [37].

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

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].

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

**4. Vaginal brachytherapy treatment in high-risk histology**

More aggressive treatments are used in uterine serous cancer (USC), clear cell carcinoma (CCC) and carcino-sarcoma (CS), which are the high risk histologies of endometrial cancer [38]. Most of the large studies including PORTEC-1, GOG 99 and PORTEC-2 [6, 8, 30] included early stage endometrial cancer patients and not high-risk patients. However, in the GOG 249 study, 20% of the patients were USC and CCC patients [37]. In a study conducted by Creasman et al., the outcomes of stage 1 high risk patients were found to be similar to those of grade 3 endometrioid type adeno-carcinoma patients [39]. Despite the presence of vaginal recurrence at a rate of 0–2.7% in stage 1–2 patients with high risk histology, the pelvic recurrence rate was found to be 0–9% [40–43]. In a study investigating USC patients, while the 5-year survival rate was 94% in patients who received VB + CT, it was 65% in patients who received LDR + EBRT but not CT [40]. In another study, USC patients

**160**

received VB + CT (six cycles of carboplatin and paclitaxel) and the vaginal, pelvic and distant metastasis rates were found to be 0, 9, and 10%, respectively, and the 5-year survival rate was 90% [41]. The effectiveness of VB alone was investigated in endometrial cancer patients with high risk histology. Some authors reported that CT did not have a great contribution [42, 43].

### **4.1 Brachytherapy for treatment of medically inoperable endometrial cancer**

As mentioned above, the standard treatment of endometrial cancer is TAH + BSO (total abdominal hysterectomy + bilateral salphingo-oopherectomy) and lymphadenectomy when indicated, however, this standard treatment cannot be performed in a group of patients due to their medical disorders and clinical performances. In these patients, definitive radiotherapy is applied for clinical stage 1 patients, neo-adjuvant therapy is applied to patients with local advanced stage disease and brachytherapy alone or radiotherapy with addition of EBRT is applied as palliative treatment in patients who have complaints such as bleeding and pelvic pain. While LDR VB+/−EBRT has been used recently in the treatment of these patients, HDR VB+/−EBRT is widely used today [44, 45]. The treatment of medically inoperable endometrial cancer patients is planned better and more effectively through advancements in radiology.

#### *4.1.1 Patient characteristics*

Medically inoperable endometrial cancer patients should be meticulously evaluated pre-operatively by a gynecologic oncologist. Most of these patients have cardiac diseases, pulmonary diseases, hypertension, diabetes mellitus, cerebro-vascular disease, renal disease, syndromes such as Marfan syndrome, advanced age and other malignancies. Morbid obesity is a relative contra-indication for the operation depending on the experience of the surgeon and the condition of the patient. Clinical performance of the patients is of vital importance as a pre-operative parameter. All of these patients should be evaluated pre-operatively for local or general anesthesia by experienced anesthetists. The hormone therapy (progestin, aromatase inhibitors) option is also available besides the radiotherapy option for clinical stage 1, grade 1 patients who are not eligible for surgery, for patients with endometrioid type endometrial cancer, for those below the age of 40 years and those willing to have a child [46]. Regression has been detected in 55% of the patients treated in this way [47].

Levonorgestrel-releasing intra-uterine devices (LNGIUDs) may be added to treatment of patients who have precancerous and stage 1, grade 1 endometrioid type endometrial cancer [48]. The patients are meticulously evaluated with CT or MRI with regard to tumor diameter, myometrial invasion depth, cervical involvement, ovarian involvement and pelvic para-aortic lymph node involvement if hormone therapy is planned, as oral regimens have the likelihood of recurrence at a rate of 25% despite the 50% or above success rates [49]. While endometrial cancer staging is done surgically according to the recent International Federation of Gynecology and Obstetrics (FIGO) 2009 classification, clinical staging is used in medically inoperable patients (**Table 3**) [50].

The patients should be meticulously evaluated for pelvic examination and distant metastasis if clinical staging would be used. Vagina, cervix and the uterus are evaluated, presence of a mass lesion is examined and the search for parametrium involvement is attempted through bimanual (rectal-vaginal) examination. Computed tomographies of the thorax, abdomen and the pelvis are performed for distant metastasis and MRI is used for assessment of the uterus and the pelvis as the negative predictive value is >85% for myometrial invasion in contrast-enhanced T2-weighted


#### **Table 3.**

*Clinical staging system for endometrial cancer.*


*CT, computed tomography; MRI, magnetic resonance imaging.*

*Note. MRI is required if a gross tumor volume is to be contoured. The clinical target volume includes the entire uterus, cervix, and upper vagina. Organs at risk include bladder, rectum, and sigmoid.*

**Table 4.**

*Recommended structures for volume-based planning in medically inoperable endometrial cancer.*

MRI and the positive predictive value is low [51]. 18-F-fluoro-deoxyglucose positron emission tomography (PET) is used for lymph node involvement [52, 53]. In a study conducted with PET-CT, the pelvic node involvement rate was 63% and the para-aortic lymph node involvement was 95% [54].
