**4. Therapeutic strategies**

#### **4.1 Molecularly targeted treatments**

One of the major challenges in endometrial cancer treatment remains the current inability to effectively prevent distant metastasis in women with deeply myoinvasive, high-grade or biologically aggressive tumors (e.g., serous and clear cell cancers). One potential target in serous tumors is HER2 [Konecny, 2009; Villella, 2006; Flemimg, 2003]. The monoclonal antibody trastuzumab binds to HER-2 and can reduce growth in cell lines that overexpress HER-2. Epidermal growth factor receptor (also known as c-erbB-1). One strategy to tackle tumor growth is to target angiogenesis,. The main factor controlling angiogenesis is VEGF. The most well known of these is bevacizumab, a monoclonal antibody against VEGF-A. A study of single-agent bevacizumab in women with recurrent endometrial cancer demonstrated a 15% response rate and a median progression-free survival of 4 months, although approximately 36% of women had a progression-free survival of 6 months [Konecny, 2009].

Prevention and Therapeutic Strategies in Endometrial Cancer 447

by many authors. A recent publication of the GOG LAP2 study has shown similar operative outcomes in the minimally invasive surgery group [Walker, 2010]. Authors have reported that the economic benefits of laparoscopy [Scribner, 1999]. Laparoscopy seems to provide equivalent results in terms of disease-free survival and overall survival compared with laparatomy, with further benefit: shorter hospital stay, less use of pain killers, lower rate of complications and improved quality of life. An increasing number of studies have shown no difference in survival or recurrence between laparoscopy and laparatomy surgery, in earlyand advanced-stage endometrial cancer [Eltabbakh, 2002; Holub, 2002; Nezhat, 2008]. Recent reports have examined robotically assisted hysterectomy in the treatment of gynecologic malignancies [Advincula, 2006]. The robotic approach could be a 'benefit' in obese women. (Boggess, 2008], but access to the high para-aortic area appears to be limited compared with the laparoscopic or open surgical approaches [Soliman, 2010]. When surgery is not feasible due to medical contraindications (5–10% of patients), external radiation therapy with or without intracavitary brachytherapy to the uterus and vagina is suitable for individual clinical use [Colombo, 2011]. In three trials women treated with laparoscopic hysterectomy were compared with 193 women treated with open surgery and there appears to be no significant difference in either disease-free or overall survival [Lin, 2008; Palomba,

The standard surgical treatment for stage I endometrial cancer is radical hysterectomy and bilateral anexectomy with or without lymphadenectomy. In young women with stage IA endometrial carcinoma is proposed to preserve fertility, based on the hysteroscopic resection of the tumor followed by hormone therapy regimen of megestrol acetate (160 mg/day) [Mazzon, 2010]. The role of systematic pelvic lymphadenectomy is in current debate. Mariani states that patients with stage I endometrial cancer, excluding stage IA–IB G1, systematic lymphadenectomy did not improve disease-free or overall survival [Mariani 2000]. In the ASTEC randomized trial, women with endometrial cancer confined to the uterus and pelvic lymphadenectomy was no evidence of benefit on overall survival or recurrence-free survival [Blake, 2009]. The authors recommended that systematic pelvic lymphadenectomy cannot be recommended in women with stage I endometrial cancer. Lymphadenectomy is highly important for determining a prognosis and in tailoring adjuvant therapies. Prognostic factors for para-aortic spread are similar to those for pelvic nodal disease and include depth of myometrial invasion and the presence of lymphovascular space invasion [Fotopoulou, 2010; Park, 2010; Nomura, 2006]. Many authors suggest a lymphadenectomy for intermediate–high risk endometrial cancer (stage IA G3 and IB) [Colombo, 2011]. Lymph node sampling did not appear to confer a survival benefit in patients with stage IA, grade 1 or 2 tumors, but improved survival in patients with grade 3 [Trimble, 1998]. External beam radiation has been shown to reduce the rate of locoregional recurrence in intermediate-risk endometrial cancer. The Postoperative Radiation Therapy in Endometrial Cancer (PORTEC) trial randomly assigned 715 women with endometrial cancer stage IB grade 2-3 tumors or stage IC grade 1-2 tumors who underwent surgery treatment to whole pelvic radiotherapy versus no further treatment. After 10 years of follow-up there was a reduction in vaginal recurrences from 15 to 4% but no difference in survival [Creutzberg, 2000]. Aalders and collaborators published the results of 540 women with stage I endometrial cancer that underwent surgical treatment and

2009].

**4.4 Surgical treatment in stage I endometrial cancer** 

A number of other antiangiogenic agents are currently being tested as single agents in Phase II trials. These include VEGF–Trap and small-molecule inhibitors of VEGF receptors [Hayes, 2009; Hayes, 2010].

One of the main challenges will be getting the more promising drugs into the clinic. Development of these newer drugs is expensive and costs will therefore be high. Whether there is a therapeutic role for lymphadenectomy in nonendometrioid tumors remains an unanswered. It has been possible to provide clear guidance with respect to the use of radiotherapy following the completion and publication of several key trials in this area, and treatment is now applied on an individualized patient basis. The investigators found that women who were normal weight and active had a reduction in risk of 73%, compared with inactive women who were overweight (BMI above 25 kg/m2). Women who were normal weight but inactive had a 55% lower risk for endometrial cancer than inactive women who were overweight. Women who were overweight but active had a 38% lower risk for endometrial cancer.

### **4.2 Treatment of localized disease**

In the case of a low-risk disease evolution, with tumor confined to the uterus, nonaggressive treatment is required, while high-risk disease require evolution untreatment multimodal radiochimiotherapy. Treatment of localized disease is mainly surgical and consists of a total hysterectomy with bilateral anexectomy as or no lymphadenectomy. The problem is the continuing debate and systematic lombo-aortic lymphadenectomy role. Lymphadenectomy can be selectively performed in women at highest risk of nodal metastases (deeply invasive or high-grade tumors) [Mariani, 2008]. Lymphadenectomy causes morbidity in approximately 11% of cases [Nunns, 2000]. In an effort to decrease the morbidity that results from lymphadenectomy, the sentinel node approach has been successfully employed. If the sentinel node is pathologically negative for metastasis, all downstream nodes should also be negative and would not require dissection. This technique yielded an overall detection rate of 82%-89% [Niikura, 2004; Delaloye, 2007]. Presently the sentinel lymph node biopsy in endometrial cancer is still an investigational technique. Studies of women undergoing full pelvic lymphadenectomy report rates of occult pelvic lymph node disease ranging from 8 to 28% depending on grade and depth of myometrial invasion [Creasman, 1987; Chi, 2008]. At present there is great uncertainty regarding what is the optimal adjuvant treatment for localized endometrial cancer. The use of adjuvant therapy for endometrial cancer depends on the patient's estimated risk of recurrence. Novel techniques for the delivery of radiation, including intensity-modulated radiation therapy and tomotherapy are promising technologies to improve the therapeutic index for patients receiving combined therapy [Lian, 2008; Salama, 2006; Beriwal, 2006]. A number of trials are ongoing to examine novel biologic and target therapies for women with endometrial cancer [Konecny, 2008; Kamat, 2007; Wright, 2007; Ozbudak, 2008; Morrison, 2006]. Systemic treatment for metastatic and relapsed disease may consist of endocrine therapy or cytotoxic chemotherapy.

#### **4.3 Surgical treatment**

The surgical approach for the treatment of endometrial cancer has traditionally been laparotomy. In the last years, the use of minimally invasive techniques is widely accepted

A number of other antiangiogenic agents are currently being tested as single agents in Phase II trials. These include VEGF–Trap and small-molecule inhibitors of VEGF receptors [Hayes,

One of the main challenges will be getting the more promising drugs into the clinic. Development of these newer drugs is expensive and costs will therefore be high. Whether there is a therapeutic role for lymphadenectomy in nonendometrioid tumors remains an unanswered. It has been possible to provide clear guidance with respect to the use of radiotherapy following the completion and publication of several key trials in this area, and treatment is now applied on an individualized patient basis. The investigators found that women who were normal weight and active had a reduction in risk of 73%, compared with inactive women who were overweight (BMI above 25 kg/m2). Women who were normal weight but inactive had a 55% lower risk for endometrial cancer than inactive women who were overweight. Women who were overweight but active had a 38% lower risk for

In the case of a low-risk disease evolution, with tumor confined to the uterus, nonaggressive treatment is required, while high-risk disease require evolution untreatment multimodal radiochimiotherapy. Treatment of localized disease is mainly surgical and consists of a total hysterectomy with bilateral anexectomy as or no lymphadenectomy. The problem is the continuing debate and systematic lombo-aortic lymphadenectomy role. Lymphadenectomy can be selectively performed in women at highest risk of nodal metastases (deeply invasive or high-grade tumors) [Mariani, 2008]. Lymphadenectomy causes morbidity in approximately 11% of cases [Nunns, 2000]. In an effort to decrease the morbidity that results from lymphadenectomy, the sentinel node approach has been successfully employed. If the sentinel node is pathologically negative for metastasis, all downstream nodes should also be negative and would not require dissection. This technique yielded an overall detection rate of 82%-89% [Niikura, 2004; Delaloye, 2007]. Presently the sentinel lymph node biopsy in endometrial cancer is still an investigational technique. Studies of women undergoing full pelvic lymphadenectomy report rates of occult pelvic lymph node disease ranging from 8 to 28% depending on grade and depth of myometrial invasion [Creasman, 1987; Chi, 2008]. At present there is great uncertainty regarding what is the optimal adjuvant treatment for localized endometrial cancer. The use of adjuvant therapy for endometrial cancer depends on the patient's estimated risk of recurrence. Novel techniques for the delivery of radiation, including intensity-modulated radiation therapy and tomotherapy are promising technologies to improve the therapeutic index for patients receiving combined therapy [Lian, 2008; Salama, 2006; Beriwal, 2006]. A number of trials are ongoing to examine novel biologic and target therapies for women with endometrial cancer [Konecny, 2008; Kamat, 2007; Wright, 2007; Ozbudak, 2008; Morrison, 2006]. Systemic treatment for metastatic and relapsed disease may consist of endocrine

The surgical approach for the treatment of endometrial cancer has traditionally been laparotomy. In the last years, the use of minimally invasive techniques is widely accepted

2009; Hayes, 2010].

endometrial cancer.

**4.2 Treatment of localized disease** 

therapy or cytotoxic chemotherapy.

**4.3 Surgical treatment** 

by many authors. A recent publication of the GOG LAP2 study has shown similar operative outcomes in the minimally invasive surgery group [Walker, 2010]. Authors have reported that the economic benefits of laparoscopy [Scribner, 1999]. Laparoscopy seems to provide equivalent results in terms of disease-free survival and overall survival compared with laparatomy, with further benefit: shorter hospital stay, less use of pain killers, lower rate of complications and improved quality of life. An increasing number of studies have shown no difference in survival or recurrence between laparoscopy and laparatomy surgery, in earlyand advanced-stage endometrial cancer [Eltabbakh, 2002; Holub, 2002; Nezhat, 2008]. Recent reports have examined robotically assisted hysterectomy in the treatment of gynecologic malignancies [Advincula, 2006]. The robotic approach could be a 'benefit' in obese women. (Boggess, 2008], but access to the high para-aortic area appears to be limited compared with the laparoscopic or open surgical approaches [Soliman, 2010]. When surgery is not feasible due to medical contraindications (5–10% of patients), external radiation therapy with or without intracavitary brachytherapy to the uterus and vagina is suitable for individual clinical use [Colombo, 2011]. In three trials women treated with laparoscopic hysterectomy were compared with 193 women treated with open surgery and there appears to be no significant difference in either disease-free or overall survival [Lin, 2008; Palomba, 2009].

#### **4.4 Surgical treatment in stage I endometrial cancer**

The standard surgical treatment for stage I endometrial cancer is radical hysterectomy and bilateral anexectomy with or without lymphadenectomy. In young women with stage IA endometrial carcinoma is proposed to preserve fertility, based on the hysteroscopic resection of the tumor followed by hormone therapy regimen of megestrol acetate (160 mg/day) [Mazzon, 2010]. The role of systematic pelvic lymphadenectomy is in current debate. Mariani states that patients with stage I endometrial cancer, excluding stage IA–IB G1, systematic lymphadenectomy did not improve disease-free or overall survival [Mariani 2000]. In the ASTEC randomized trial, women with endometrial cancer confined to the uterus and pelvic lymphadenectomy was no evidence of benefit on overall survival or recurrence-free survival [Blake, 2009]. The authors recommended that systematic pelvic lymphadenectomy cannot be recommended in women with stage I endometrial cancer. Lymphadenectomy is highly important for determining a prognosis and in tailoring adjuvant therapies. Prognostic factors for para-aortic spread are similar to those for pelvic nodal disease and include depth of myometrial invasion and the presence of lymphovascular space invasion [Fotopoulou, 2010; Park, 2010; Nomura, 2006]. Many authors suggest a lymphadenectomy for intermediate–high risk endometrial cancer (stage IA G3 and IB) [Colombo, 2011]. Lymph node sampling did not appear to confer a survival benefit in patients with stage IA, grade 1 or 2 tumors, but improved survival in patients with grade 3 [Trimble, 1998]. External beam radiation has been shown to reduce the rate of locoregional recurrence in intermediate-risk endometrial cancer. The Postoperative Radiation Therapy in Endometrial Cancer (PORTEC) trial randomly assigned 715 women with endometrial cancer stage IB grade 2-3 tumors or stage IC grade 1-2 tumors who underwent surgery treatment to whole pelvic radiotherapy versus no further treatment. After 10 years of follow-up there was a reduction in vaginal recurrences from 15 to 4% but no difference in survival [Creutzberg, 2000]. Aalders and collaborators published the results of 540 women with stage I endometrial cancer that underwent surgical treatment and

Prevention and Therapeutic Strategies in Endometrial Cancer 449

Maximal surgical debunking is imperative in patients with a good performance status. The surgical approach consists of anterior and posterior pelvic exenteration. For distant metastatic disease, palliative surgery could be considered in patients with a good performance. If positive nodes: radiotherapy. If metastatic disease: chemotherapy– radiotherapy for palliative treatment [Colombo, 2011]. Traditionally, treatment for women with stage III endometrial cancer has relied on radiotherapy while women with stage IV disease have been treated with palliative chemotherapy [Ross, 2008; Denschlag, 2007; Mariani, 2006]. 396 women with stage III or IV disease were randomized to postoperative whole abdominal radiation versus chemotherapy with doxorubicin and cisplatin. Patients in the chemotherapy group had a statistically significant increased progression-free (42 vs 38%) and overall survival (53 vs 42%) [Gallion, 2003]. Agents for endometrial cancer appear to be doxorubicin and cisplatin. Response rates to single-agent doxorubicin alone are generally in the range of 17-25% [Carey, 2006; Gallion, 2003]. Two prospective randomized trials have demonstrated a superior response rate to doxorubicin and cisplatin as compared with doxorubicin alone, however, with similar survival rates [Thigpen, 1994; Thigpen, 2004, Aapro, 2003]. When carboplatin is associated with cisplatin, is reported a response rate of greater than 40% [Akram, 2005; Dimopoulos, 2000; Sovak, 2006; Secord, 2007]. Given this provocative data, doxorubicin plus paclitaxel was investigated by the GOG (GOG 163) as an alternative to doxorubicin and cisplatin for women with advanced or recurrent disease. Doxorubicin, cisplatin and paclitaxel demonstrated a significant improvement in response rate, progression free and overall survival, but toxicity was much higher with the three drug regimen [Fleming, 2004]. The combination with cisplatin and doxorubicin or cisplatin, doxorubicin and paclitaxel for women with stage III and IV completely resected endometrial cancer appeared equivalent [Alvarez, 2007; Bruzzone, 2004]. Patients with stage IIIC underwent adjuvant treatment with paclitaxel and concurrent pelvic radiation therapy. Overall survival was 81% at 3 years with a median time to relapse of 19 months [Mangili, 2006]. In a similar design, Greven and colleagues reported on 46 patients with endometrial adenocarcinoma with greater than 50% myometrial invasion, stromal invasion of the cervix, or extrauterine disease confined to the pelvis and/or positive peritoneal cytology that underwent postoperative adjuvant treatment with pelvic radiation therapy, vaginal brachytherapy and concurrent cisplatin and paclitaxel. Survival at 4 years was 85% [Greven,

Radiation therapy is standard treatment for vaginal recurrence (external beam plus vaginal brachytherapy). There is high rates in local control, complete response (CR) and 5-year survival is 50%. Surgery is the treatment of choice for pelvic recurrence, or radiation therapy, while for regional pelvic recurrences it is radiation therapy, associated if possible

The combination of Doxorubicin, Cisplatin, and Paclitaxel was found to produce an improvement in progression free survival for patients with recurrent endometrial cancer, compared with the two drug combination of Doxorubicin and Cisplatin [Fleming, 2000]. When using adjuvant chemotherapy without adjuvant radiation therapy in patients with advanced-stage endometrial cancer, 40% of women experienced a pelvic relapse at 3 years

**4.6 Surgical treatment in stage III-IV endometrial cancer** 

2006].

**4.7 Locoregional recurrence** 

with chemotherapy.

vaginal brachytherapy and were randomized to whole pelvic radiation versus observation. Pelvic control was improved with the addition of radiotherapy, but there were no survival differences at 5 years [Aalders, 1980]. Nout publish the results of a randomized clinical trial (PORTEC-2) comparing vaginal brachytherapy and external beam radiation in intermediaterisk patients [Nout, 2010]. This study showed no any difference in overall survival or progression-free survival (PFS). The quality of life was better in the vaginal brachytherapy treatment. Radiation of patients who underwent hysterectomy with comprehensive lymphadenectomy improves local control and disease-free survival, but did not affect overall survival. (Keys, 2004) but is associated with appreciable toxicity [Creutzberg, 2000; Keys, 2004]. ESMO Guidelines Working Group 2011 recommended in stage IB G1-2 with negative prognostic factors pelvic radiotherapy and/or adjunctive chemotherapy could be considered [Colombo, 2011]. Endometrial cancer stage I with grade 3 tumors combination chemotherapy to pelvic radiotherapy require. Platinum-based chemotherapy can be considered in stage I G3 with adverse risk factors (patient age, lymphovascular space invasion and high tumor volume) platinum-based adjuvant chemotherapy for early (stage I) disease improves PFS and overall survival. Two trials, one Italian and one Japanese in highrisk patients comparing five courses of cisplatin, doxorubicin and cyclophosphamide with external pelvic radiation reported no difference between therapies in terms of PFS or overall survival [Maggi, 2006; Susumu, 2008]. Chemotherapy appeared superior to pelvic radiotherapy in patients with stage IC, aged >70 years with outer half myometrial invasion, with grade 3, or with stage I disease and positive peritoneal cytology [Maggi, 2006]. In a Cochrane Collaboration review of adjuvant radiotherapy for stage I, external-beam radiotherapy resulted in a 72% reduction in pelvic relapses, a reduction in death in patients with multiple high-risk factors (stage IC and grade 3 tumors) did not translate into a reduction in distant metastatic [Kong, 2007].

#### **4.5 Surgical treatment in stage II endometrial cancer**

Traditionally, the surgical approach consists of radical hysterectomy with bilateral salpingooophorectomy and systematic pelvic lymphadenectomy with or without paraaortic lymphadenectomy. In stage II, lymphadenectomy is essential to guide surgical staging and adjuvant therapy. Para-aortic dissection should aim to remove the nodes to level of the mesenteric artery up to the renal vessels, rather than restricting dissection to the level of the inferior mesenteric artery. Large retrospective nonrandomized studies demonstrated that women, who have a para-aortic dissection, have improved outcomes, with increased overall survival [Chan, 2006; Chan, 2007]. Authors show that women at intermediate or high risk of disease recurrence should have pelvic and para-aortic lymphadenectomy and no benefit was seen in low-risk patients [Todo, 2010]. ESMO suggests that adjuvant treatment in stage II consists of pelvic radiotherapy and vaginal brachytherapy. If prognostic factors (grade 1–2 tumor, myometrial invasion <50%, LVSI and complete surgical staging) are negativebrachytherapy alone. If prognostic factors are negative it is feasible chemotherapy with/without radiation [Colombo, 2011].

Chemotherapy appeared superior to pelvic radiotherapy in patients with stage II with a significantly higher overall survival and progression-free survival and the rate of pelvic recurrence was the same (7%). (Susumu, 2008) Platinum-based chemotherapy can be considered in this stage. In retrospective series that platinum-based adjuvant chemotherapy for stage II disease improves PFS and overall survival [Soliman, 2010].

vaginal brachytherapy and were randomized to whole pelvic radiation versus observation. Pelvic control was improved with the addition of radiotherapy, but there were no survival differences at 5 years [Aalders, 1980]. Nout publish the results of a randomized clinical trial (PORTEC-2) comparing vaginal brachytherapy and external beam radiation in intermediaterisk patients [Nout, 2010]. This study showed no any difference in overall survival or progression-free survival (PFS). The quality of life was better in the vaginal brachytherapy treatment. Radiation of patients who underwent hysterectomy with comprehensive lymphadenectomy improves local control and disease-free survival, but did not affect overall survival. (Keys, 2004) but is associated with appreciable toxicity [Creutzberg, 2000; Keys, 2004]. ESMO Guidelines Working Group 2011 recommended in stage IB G1-2 with negative prognostic factors pelvic radiotherapy and/or adjunctive chemotherapy could be considered [Colombo, 2011]. Endometrial cancer stage I with grade 3 tumors combination chemotherapy to pelvic radiotherapy require. Platinum-based chemotherapy can be considered in stage I G3 with adverse risk factors (patient age, lymphovascular space invasion and high tumor volume) platinum-based adjuvant chemotherapy for early (stage I) disease improves PFS and overall survival. Two trials, one Italian and one Japanese in highrisk patients comparing five courses of cisplatin, doxorubicin and cyclophosphamide with external pelvic radiation reported no difference between therapies in terms of PFS or overall survival [Maggi, 2006; Susumu, 2008]. Chemotherapy appeared superior to pelvic radiotherapy in patients with stage IC, aged >70 years with outer half myometrial invasion, with grade 3, or with stage I disease and positive peritoneal cytology [Maggi, 2006]. In a Cochrane Collaboration review of adjuvant radiotherapy for stage I, external-beam radiotherapy resulted in a 72% reduction in pelvic relapses, a reduction in death in patients with multiple high-risk factors (stage IC and grade 3 tumors) did not translate into a

Traditionally, the surgical approach consists of radical hysterectomy with bilateral salpingooophorectomy and systematic pelvic lymphadenectomy with or without paraaortic lymphadenectomy. In stage II, lymphadenectomy is essential to guide surgical staging and adjuvant therapy. Para-aortic dissection should aim to remove the nodes to level of the mesenteric artery up to the renal vessels, rather than restricting dissection to the level of the inferior mesenteric artery. Large retrospective nonrandomized studies demonstrated that women, who have a para-aortic dissection, have improved outcomes, with increased overall survival [Chan, 2006; Chan, 2007]. Authors show that women at intermediate or high risk of disease recurrence should have pelvic and para-aortic lymphadenectomy and no benefit was seen in low-risk patients [Todo, 2010]. ESMO suggests that adjuvant treatment in stage II consists of pelvic radiotherapy and vaginal brachytherapy. If prognostic factors (grade 1–2 tumor, myometrial invasion <50%, LVSI and complete surgical staging) are negativebrachytherapy alone. If prognostic factors are negative it is feasible chemotherapy

Chemotherapy appeared superior to pelvic radiotherapy in patients with stage II with a significantly higher overall survival and progression-free survival and the rate of pelvic recurrence was the same (7%). (Susumu, 2008) Platinum-based chemotherapy can be considered in this stage. In retrospective series that platinum-based adjuvant chemotherapy

for stage II disease improves PFS and overall survival [Soliman, 2010].

reduction in distant metastatic [Kong, 2007].

with/without radiation [Colombo, 2011].

**4.5 Surgical treatment in stage II endometrial cancer** 

### **4.6 Surgical treatment in stage III-IV endometrial cancer**

Maximal surgical debunking is imperative in patients with a good performance status. The surgical approach consists of anterior and posterior pelvic exenteration. For distant metastatic disease, palliative surgery could be considered in patients with a good performance. If positive nodes: radiotherapy. If metastatic disease: chemotherapy– radiotherapy for palliative treatment [Colombo, 2011]. Traditionally, treatment for women with stage III endometrial cancer has relied on radiotherapy while women with stage IV disease have been treated with palliative chemotherapy [Ross, 2008; Denschlag, 2007; Mariani, 2006]. 396 women with stage III or IV disease were randomized to postoperative whole abdominal radiation versus chemotherapy with doxorubicin and cisplatin. Patients in the chemotherapy group had a statistically significant increased progression-free (42 vs 38%) and overall survival (53 vs 42%) [Gallion, 2003]. Agents for endometrial cancer appear to be doxorubicin and cisplatin. Response rates to single-agent doxorubicin alone are generally in the range of 17-25% [Carey, 2006; Gallion, 2003]. Two prospective randomized trials have demonstrated a superior response rate to doxorubicin and cisplatin as compared with doxorubicin alone, however, with similar survival rates [Thigpen, 1994; Thigpen, 2004, Aapro, 2003]. When carboplatin is associated with cisplatin, is reported a response rate of greater than 40% [Akram, 2005; Dimopoulos, 2000; Sovak, 2006; Secord, 2007]. Given this provocative data, doxorubicin plus paclitaxel was investigated by the GOG (GOG 163) as an alternative to doxorubicin and cisplatin for women with advanced or recurrent disease. Doxorubicin, cisplatin and paclitaxel demonstrated a significant improvement in response rate, progression free and overall survival, but toxicity was much higher with the three drug regimen [Fleming, 2004]. The combination with cisplatin and doxorubicin or cisplatin, doxorubicin and paclitaxel for women with stage III and IV completely resected endometrial cancer appeared equivalent [Alvarez, 2007; Bruzzone, 2004]. Patients with stage IIIC underwent adjuvant treatment with paclitaxel and concurrent pelvic radiation therapy. Overall survival was 81% at 3 years with a median time to relapse of 19 months [Mangili, 2006]. In a similar design, Greven and colleagues reported on 46 patients with endometrial adenocarcinoma with greater than 50% myometrial invasion, stromal invasion of the cervix, or extrauterine disease confined to the pelvis and/or positive peritoneal cytology that underwent postoperative adjuvant treatment with pelvic radiation therapy, vaginal brachytherapy and concurrent cisplatin and paclitaxel. Survival at 4 years was 85% [Greven, 2006].

#### **4.7 Locoregional recurrence**

Radiation therapy is standard treatment for vaginal recurrence (external beam plus vaginal brachytherapy). There is high rates in local control, complete response (CR) and 5-year survival is 50%. Surgery is the treatment of choice for pelvic recurrence, or radiation therapy, while for regional pelvic recurrences it is radiation therapy, associated if possible with chemotherapy.

The combination of Doxorubicin, Cisplatin, and Paclitaxel was found to produce an improvement in progression free survival for patients with recurrent endometrial cancer, compared with the two drug combination of Doxorubicin and Cisplatin [Fleming, 2000]. When using adjuvant chemotherapy without adjuvant radiation therapy in patients with advanced-stage endometrial cancer, 40% of women experienced a pelvic relapse at 3 years

Prevention and Therapeutic Strategies in Endometrial Cancer 451

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