Review Article J Gynecol Oncol Vol. 25, No. 2:136-147 http://dx.doi.org/10.3802/jgo.2014.25.2.136 pISSN 2005-0380·eISSN 2005-0399
Adjuvant therapy for endometrial cancer Maria C. DeLeon1, Natraj R. Ammakkanavar2, Daniela Matei1-5
Departments of 1Obstetrics and Gynecology, 2Medicine, and 3Biochemistry and Molecular Biology, 4Melvin and Bren Simon Cancer Center, 5VA Roudebush Hospital, Indiana University School of Medicine, Indianapolis, IN, USA
Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. Keywords: Adjuvant therapy, Early stage, Endometrial cancer, Locally advanced, Risk stratification
INTRODUCTION Endometrial cancer (EC) is the most common gynecologic malignancy in the United States and the sixth most common cancer worldwide. In the world, the highest incidence of EC is recorded in North America, followed by Central and Eastern Europe, while the lowest incidence is found in developing countries in Mid- and Western Africa [1]. In the United States approximately 47,000 new cases of uterine cancer and 8,000 related deaths are reported yearly [2]. Based on clinical characteristics that are mirrored by distinct molecular features, two types of uterine cancer are recognized. Type I EC which is more common, representing 80% of cases, is estrogen dependent, and routinely diagnosed at an early stage. Type I EC usually occurs in premenopausal women and has an excellent prognosis. Risk factors include obesity, chronic anovulation
Received Dec 23, 2013, Accepted Jan 19, 2014 This review was solicited and has not been peer reviewed. Correspondence to Daniela Matei Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA. E-mail: [email protected]
such as that induced by polycystic ovary syndrome, exposure to estrogen or tamoxifen, nulliparity, early menarche and late menopause. Type I EC is characterized molecularly by expression of the estrogen receptors (ER) and progesterone receptors, alterations of the PI3K/AKT pathway through activating mutations of the kinases or loss of the phosphatase PTEN, presence of multisatellite instability and β-catenin mutations [3]. Type II EC which is less common, representing up to 20% of all cases, is more aggressive, not driven by estrogen and occurs in thinner and older women, most commonly after menopause [4]. This type includes high grade endometrioid tumors, and the aggressive variant histologic types, serous and clear cell carcinoma. Molecularly, type II EC is characterized by loss of function mutations affecting p53 and p16 and can harbor Her 2/neu amplification [3]. The surgico-pathologic system for staging was introduced in 1988 by the International Federation of Gynecology and Obstetrics (FIGO) and a recent revision was adopted in 2009 (Table 1) [5]. The revised staging system intends to provide improved prognostic accuracy relative to the extent of disease, based on refinement of risk stratification models during the past 20 years [5]. The standard surgical staging procedure for EC includes total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), peritoneal washings, and
Copyright © 2014. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
www.ejgo.org
Adjuvant treatment for endometrial cancer
Table 1. Comparison between FIGO staging systems 1988 and 2009 Stage
FIGO 1988*
FIGO 2009 [5]
I
a: Tumor limited to endometrium b: Invasion to less than half of myometrium c: Invasion equal to or more than half of myometrium
A: Tumor limited to endometrium or invasion to less than half of myometrium B: Invasion equal to or more than half of myometrium
II
a: Endocervical glandular involvement only b: Cervical stromal invasion
III
a: Tumor invades the serosa of the corpus uteri and/or adnexae and/or positive cytological findings b: Vaginal metastasis c: Metastatic to pelvic and/or para-aortic lymph nodes
A: Tumor Invades the serosa and/or adnexae B: Vaginal and/or parametrial involvement C1: Metastasis to pelvic lymph nodes C2: Metastasis to Para-aortic lymph nodes
IV
a: Tumor invasion of bladder and/or bowel mucosa b: Distant metastases, including intra-abdominal metastasis and/or inguinal lymph nodes
A: Tumor invasion of bladder and/or bowel mucosa B: Distant metastases, including intra-abdominal metastasis and/or inguinal lymph nodes
Tumor invades cervical stroma, but does not extend beyond the uterus
*Adapted after the International Federation of Gynecology and Obstetrics (FIGO) nomenclature, Rio de Janeiro, 1988.
pelvic and para-aortic lymphadenectomy. The routine performance of pelvic and para-aortic lymphadenectomy remains controversial as the procedures adds surgical risks and its therapeutic benefit has not been proven in randomized controlled trials [6]. However the dissection of pelvic and paraaortic lymph nodes provides key prognostic information that critically influences postoperative therapy [7]. Stage remains the most important prognostic factor for EC, early stage patients having the best outcomes and survival decreases with advancing stage. Overall the 5-year survival rates for all grades and histologic subtypes are approximately 78%-90% for stage I, 74% for stage II, 36%-57% for stage III, and 20% for stage IV [8]. In addition to the lymph node status, the tumor histologic type, grade, depth of myometrial invasion, and the presence of lymphovascular invasion are factors used to assess the risk of recurrence and the need for adjuvant treatment [9].
TREATMENT FOR EARLY STAGE ENDOMETRIAL CANCER (STAGES I-II) Adjuvant therapy for patients with early stage disease is tailored according to the estimated risk of recurrence, which is defined according to FIGO stage and compiled histological factors. Based on retrospective histopathological analyses [1012] and prospective adjuvant studies for patients with stage I/ II EC, three risk groups were characterized: low, intermediate, and high risk. A summary of clinical trials evaluating adjuvant therapy in early stage EC is included in Table 2 [13-20]. 1. Risk stratification for early stage EC The low risk group includes patients with endometrium-con fined disease and well or moderately differentiated tumors.
J Gynecol Oncol Vol. 25, No. 2:136-147
These patients have a very low risk of recurrence and do not require adjuvant treatment. External beam radiation (EBRT) to the pelvis is associated with more risk than benefit and confers no survival advantage. A meta-analysis of 8 studies showed that women younger than 60 years of age who were treated with EBRT had higher risk of developing secondary malignancies (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.3 to 3.15), higher risk of mortality (HR, 1.36; 95% CI, 1.06 to 1.76) and had experienced lower quality of life from significant radiation toxicity [21]. Therefore, patients in the low risk category do not generally receive adjuvant treatment, but are followed-up carefully during the surveillance period. The intermediate risk group comprises patients with evidence of myometrial invasion (stage IA/IB) or those with disease extending into the cervical stroma (stage II). The intermediate risk group was further subdivided into low intermediate and high intermediate risk (HIR) groups based on an analysis of patients enrolled in the protocol of the Gynecologic Oncology Group (GOG) 99. The HIR groups was defined according to age and three pathological criteria: histologic grades 2 or 3, presence of lymphovascular invasion and invasion of the outer third of myometrium. The HIR group includes patients older than 70 meeting one of the specified pathological criteria, patients between 50-69 years of age displaying 2 of the 3 pathological criteria and patients younger than 50 years of age fulfilling all three criteria [15]. A benefit from adjuvant EBRT was demonstrated for the HIR group, but not for patients in the low intermediate risk group. 2. Radiation in early stage EC The effects of adjuvant pelvic radiation (PRT) for the intermediate risk group were studied in several trials, including the Oslo trial, the Postoperative Radiation Therapy for Endometrial
www.ejgo.org 137
Maria C. DeLeon, et al.
Table 2. Summary of clinical trials investigating adjuvant therapy for early stage EC Eligibility
Primary endpoint
Study
No.
Treatment arms
Results (%)
Aalders et al. (1968-1974) [13]
540
PRT vs. observation
TAH/BSO followed by Ra-ICRT to vaginal mucosa clinical stage I
LRR, OS
9 yr LRR: 1.9 vs. 6.9 (S) 9 yr OS: 90 vs. 87 (NS)
PORTEC-1 (1990-1997) [14] Long term follow-up (1990-2008)
714
PRT vs. observation
TAH/BSO; All histologies Grade 1 with ≥50% myometrial invasion OR Grade 2 with any invasion OR Grade 3 with 50% myometrial invasion)
LRR
5 yr vaginal relapse: 1.6 vs. 1.8 (NS) 5 yr LRR: 2.1 vs. 5.1 (NS) 5 yr OS: 79.6 vs. 82.7
ASTEC/EN.5 (MRC-NCIC Intergroup trial) (1996-2005) [17]
905
PRT vs. observation VBT allowed
TAH/BSO Stage IA (grade 3), stage IB (grade 3), stage IC, or stage IIA Early stage papillary serous or clear cell of any grade
OS
5 yr LRR: 3.2 vs. 6.1 (NS) 5 yr OS: 83.9 vs. 83.5 (NS)
Sorbe et al. (1997-2008) [18]
527
PRT+VBT vs. VBT
TAH/BSO, node sampling Stage I with 1 of the following risk factors: grade 3, ≥50% myometrial invasion or DNA aneuploidy; negative peritoneal cytology and lymph nodes
LRR, OS
5 yr LRR: 1.5 vs. 5 (S) 5 yr OS: 89 vs. 90 (NS)
JGOG 2033 (1994-2000) [19]
385
PRT vs. CAP
TAH/BSO, pelvic lymphadenectomy Stage IC-IIIC with >50% myometrial invasion
PFS, OS
5 yr PFS: 83.5 vs. 81.8 (NS) HIR: 66 vs. 84 (S) 5 yr OS: 85.3 vs. 86.7 (NS) HIR: 74 vs. 90 (S)
Soderini et al. (1995-2001) [20]
123
PRT vs. observation
Complete surgical staging Stage IB (grade 2-3), stage IC
PFS, OS
OS: 92 vs. 80 (NS) PFS: 88 vs. 79 (NS)
CAP, Cyclophosphamide/Doxorubicin/Cisplatin; EC, endometrial cancer; GOG, Gynecologic Oncology Group; HIR, high intermediate risk group; JGOG, Japanese Gynecologic Oncology Group; LRR, locoregional recurrence; MRC-NCIC, Medical Research Council-National Cancer Institute of Canada; NS, statistically non-significant; OS, overall survival; PFS, progression-free survival; PORTEC, Postoperative Radiation Therapy for Endometrial Cancer; PRT, pelvic external beam radiation therapy; Ra-ICRT, radium intra-cavitary radiotherapy; S, statistically significant; TAH/ BSO, total abdominal hysterectomy with bilateral salpingo-oophorectomy; VBT, vaginal brachytherapy.
Cancer (PORTEC) 1 trial, protocol GOG 99, and others. The first randomized control trial to show that adjuvant radiation provides locoregional control in early stage EC was published in 1980 by Aalders et al. [13] All patients enrolled in that trial underwent TAH, BSO, but not lymph node dissection. Patients included in the study had stage I disease, all received intracavitary radium and were randomized to either additional PRT or no further treatment. PRT provided better local control compared to observation (1.9% vs. 6.9%; p50% myometrial invasion
PRT vs. CT(CAP)
NSGO/EORTC (1996-2007) [29]
383
Stage I-III (high risk profile)
PRT vs. PRT+CT(M)
PFS
5 yr PFS: 72 vs. 79 (p=0.04) 5 yr OS: 76 vs. 83 (NS)
MaNGO ILIADE-3 (1998-2007) [29]
157
Stage IIB-IIIC Serous/clear cell histology excluded
PRT vs. PRT+CT(CD)
PFS
5 yr PFS: 61 vs. 74 (NS) 5 yr OS: 73 vs. 78 (NS)
GOG 184 (2000-2004) [41]
552
Optimally debulked Stage III-IV
VD-RT+CD vs. VD-RT+CDP
RFS
3 yr PFS: 62 vs. 64 (NS)
GOG 258 (2009-present)
804
Optimally debulked Stage III-IVa Stage I-II disease-serous or clear cell histology
VD-RT/cisplatin+CP (4 cycles) vs. CP (6 cycles)
RFS
Ongoing study
Stage I-III (high risk profile)
PRT vs. PRT/cisplatin+CP (4 cycles)
OS, FFS
Ongoing study
PORTEC III (2006-present)
PFS, OS
5 yr PFS: 38 vs. 42 (p
Adjuvant therapy for endometrial cancer Maria C. DeLeon1, Natraj R. Ammakkanavar2, Daniela Matei1-5
Departments of 1Obstetrics and Gynecology, 2Medicine, and 3Biochemistry and Molecular Biology, 4Melvin and Bren Simon Cancer Center, 5VA Roudebush Hospital, Indiana University School of Medicine, Indianapolis, IN, USA
Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. Keywords: Adjuvant therapy, Early stage, Endometrial cancer, Locally advanced, Risk stratification
INTRODUCTION Endometrial cancer (EC) is the most common gynecologic malignancy in the United States and the sixth most common cancer worldwide. In the world, the highest incidence of EC is recorded in North America, followed by Central and Eastern Europe, while the lowest incidence is found in developing countries in Mid- and Western Africa [1]. In the United States approximately 47,000 new cases of uterine cancer and 8,000 related deaths are reported yearly [2]. Based on clinical characteristics that are mirrored by distinct molecular features, two types of uterine cancer are recognized. Type I EC which is more common, representing 80% of cases, is estrogen dependent, and routinely diagnosed at an early stage. Type I EC usually occurs in premenopausal women and has an excellent prognosis. Risk factors include obesity, chronic anovulation
Received Dec 23, 2013, Accepted Jan 19, 2014 This review was solicited and has not been peer reviewed. Correspondence to Daniela Matei Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA. E-mail: [email protected]
such as that induced by polycystic ovary syndrome, exposure to estrogen or tamoxifen, nulliparity, early menarche and late menopause. Type I EC is characterized molecularly by expression of the estrogen receptors (ER) and progesterone receptors, alterations of the PI3K/AKT pathway through activating mutations of the kinases or loss of the phosphatase PTEN, presence of multisatellite instability and β-catenin mutations [3]. Type II EC which is less common, representing up to 20% of all cases, is more aggressive, not driven by estrogen and occurs in thinner and older women, most commonly after menopause [4]. This type includes high grade endometrioid tumors, and the aggressive variant histologic types, serous and clear cell carcinoma. Molecularly, type II EC is characterized by loss of function mutations affecting p53 and p16 and can harbor Her 2/neu amplification [3]. The surgico-pathologic system for staging was introduced in 1988 by the International Federation of Gynecology and Obstetrics (FIGO) and a recent revision was adopted in 2009 (Table 1) [5]. The revised staging system intends to provide improved prognostic accuracy relative to the extent of disease, based on refinement of risk stratification models during the past 20 years [5]. The standard surgical staging procedure for EC includes total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), peritoneal washings, and
Copyright © 2014. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
www.ejgo.org
Adjuvant treatment for endometrial cancer
Table 1. Comparison between FIGO staging systems 1988 and 2009 Stage
FIGO 1988*
FIGO 2009 [5]
I
a: Tumor limited to endometrium b: Invasion to less than half of myometrium c: Invasion equal to or more than half of myometrium
A: Tumor limited to endometrium or invasion to less than half of myometrium B: Invasion equal to or more than half of myometrium
II
a: Endocervical glandular involvement only b: Cervical stromal invasion
III
a: Tumor invades the serosa of the corpus uteri and/or adnexae and/or positive cytological findings b: Vaginal metastasis c: Metastatic to pelvic and/or para-aortic lymph nodes
A: Tumor Invades the serosa and/or adnexae B: Vaginal and/or parametrial involvement C1: Metastasis to pelvic lymph nodes C2: Metastasis to Para-aortic lymph nodes
IV
a: Tumor invasion of bladder and/or bowel mucosa b: Distant metastases, including intra-abdominal metastasis and/or inguinal lymph nodes
A: Tumor invasion of bladder and/or bowel mucosa B: Distant metastases, including intra-abdominal metastasis and/or inguinal lymph nodes
Tumor invades cervical stroma, but does not extend beyond the uterus
*Adapted after the International Federation of Gynecology and Obstetrics (FIGO) nomenclature, Rio de Janeiro, 1988.
pelvic and para-aortic lymphadenectomy. The routine performance of pelvic and para-aortic lymphadenectomy remains controversial as the procedures adds surgical risks and its therapeutic benefit has not been proven in randomized controlled trials [6]. However the dissection of pelvic and paraaortic lymph nodes provides key prognostic information that critically influences postoperative therapy [7]. Stage remains the most important prognostic factor for EC, early stage patients having the best outcomes and survival decreases with advancing stage. Overall the 5-year survival rates for all grades and histologic subtypes are approximately 78%-90% for stage I, 74% for stage II, 36%-57% for stage III, and 20% for stage IV [8]. In addition to the lymph node status, the tumor histologic type, grade, depth of myometrial invasion, and the presence of lymphovascular invasion are factors used to assess the risk of recurrence and the need for adjuvant treatment [9].
TREATMENT FOR EARLY STAGE ENDOMETRIAL CANCER (STAGES I-II) Adjuvant therapy for patients with early stage disease is tailored according to the estimated risk of recurrence, which is defined according to FIGO stage and compiled histological factors. Based on retrospective histopathological analyses [1012] and prospective adjuvant studies for patients with stage I/ II EC, three risk groups were characterized: low, intermediate, and high risk. A summary of clinical trials evaluating adjuvant therapy in early stage EC is included in Table 2 [13-20]. 1. Risk stratification for early stage EC The low risk group includes patients with endometrium-con fined disease and well or moderately differentiated tumors.
J Gynecol Oncol Vol. 25, No. 2:136-147
These patients have a very low risk of recurrence and do not require adjuvant treatment. External beam radiation (EBRT) to the pelvis is associated with more risk than benefit and confers no survival advantage. A meta-analysis of 8 studies showed that women younger than 60 years of age who were treated with EBRT had higher risk of developing secondary malignancies (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.3 to 3.15), higher risk of mortality (HR, 1.36; 95% CI, 1.06 to 1.76) and had experienced lower quality of life from significant radiation toxicity [21]. Therefore, patients in the low risk category do not generally receive adjuvant treatment, but are followed-up carefully during the surveillance period. The intermediate risk group comprises patients with evidence of myometrial invasion (stage IA/IB) or those with disease extending into the cervical stroma (stage II). The intermediate risk group was further subdivided into low intermediate and high intermediate risk (HIR) groups based on an analysis of patients enrolled in the protocol of the Gynecologic Oncology Group (GOG) 99. The HIR groups was defined according to age and three pathological criteria: histologic grades 2 or 3, presence of lymphovascular invasion and invasion of the outer third of myometrium. The HIR group includes patients older than 70 meeting one of the specified pathological criteria, patients between 50-69 years of age displaying 2 of the 3 pathological criteria and patients younger than 50 years of age fulfilling all three criteria [15]. A benefit from adjuvant EBRT was demonstrated for the HIR group, but not for patients in the low intermediate risk group. 2. Radiation in early stage EC The effects of adjuvant pelvic radiation (PRT) for the intermediate risk group were studied in several trials, including the Oslo trial, the Postoperative Radiation Therapy for Endometrial
www.ejgo.org 137
Maria C. DeLeon, et al.
Table 2. Summary of clinical trials investigating adjuvant therapy for early stage EC Eligibility
Primary endpoint
Study
No.
Treatment arms
Results (%)
Aalders et al. (1968-1974) [13]
540
PRT vs. observation
TAH/BSO followed by Ra-ICRT to vaginal mucosa clinical stage I
LRR, OS
9 yr LRR: 1.9 vs. 6.9 (S) 9 yr OS: 90 vs. 87 (NS)
PORTEC-1 (1990-1997) [14] Long term follow-up (1990-2008)
714
PRT vs. observation
TAH/BSO; All histologies Grade 1 with ≥50% myometrial invasion OR Grade 2 with any invasion OR Grade 3 with 50% myometrial invasion)
LRR
5 yr vaginal relapse: 1.6 vs. 1.8 (NS) 5 yr LRR: 2.1 vs. 5.1 (NS) 5 yr OS: 79.6 vs. 82.7
ASTEC/EN.5 (MRC-NCIC Intergroup trial) (1996-2005) [17]
905
PRT vs. observation VBT allowed
TAH/BSO Stage IA (grade 3), stage IB (grade 3), stage IC, or stage IIA Early stage papillary serous or clear cell of any grade
OS
5 yr LRR: 3.2 vs. 6.1 (NS) 5 yr OS: 83.9 vs. 83.5 (NS)
Sorbe et al. (1997-2008) [18]
527
PRT+VBT vs. VBT
TAH/BSO, node sampling Stage I with 1 of the following risk factors: grade 3, ≥50% myometrial invasion or DNA aneuploidy; negative peritoneal cytology and lymph nodes
LRR, OS
5 yr LRR: 1.5 vs. 5 (S) 5 yr OS: 89 vs. 90 (NS)
JGOG 2033 (1994-2000) [19]
385
PRT vs. CAP
TAH/BSO, pelvic lymphadenectomy Stage IC-IIIC with >50% myometrial invasion
PFS, OS
5 yr PFS: 83.5 vs. 81.8 (NS) HIR: 66 vs. 84 (S) 5 yr OS: 85.3 vs. 86.7 (NS) HIR: 74 vs. 90 (S)
Soderini et al. (1995-2001) [20]
123
PRT vs. observation
Complete surgical staging Stage IB (grade 2-3), stage IC
PFS, OS
OS: 92 vs. 80 (NS) PFS: 88 vs. 79 (NS)
CAP, Cyclophosphamide/Doxorubicin/Cisplatin; EC, endometrial cancer; GOG, Gynecologic Oncology Group; HIR, high intermediate risk group; JGOG, Japanese Gynecologic Oncology Group; LRR, locoregional recurrence; MRC-NCIC, Medical Research Council-National Cancer Institute of Canada; NS, statistically non-significant; OS, overall survival; PFS, progression-free survival; PORTEC, Postoperative Radiation Therapy for Endometrial Cancer; PRT, pelvic external beam radiation therapy; Ra-ICRT, radium intra-cavitary radiotherapy; S, statistically significant; TAH/ BSO, total abdominal hysterectomy with bilateral salpingo-oophorectomy; VBT, vaginal brachytherapy.
Cancer (PORTEC) 1 trial, protocol GOG 99, and others. The first randomized control trial to show that adjuvant radiation provides locoregional control in early stage EC was published in 1980 by Aalders et al. [13] All patients enrolled in that trial underwent TAH, BSO, but not lymph node dissection. Patients included in the study had stage I disease, all received intracavitary radium and were randomized to either additional PRT or no further treatment. PRT provided better local control compared to observation (1.9% vs. 6.9%; p50% myometrial invasion
PRT vs. CT(CAP)
NSGO/EORTC (1996-2007) [29]
383
Stage I-III (high risk profile)
PRT vs. PRT+CT(M)
PFS
5 yr PFS: 72 vs. 79 (p=0.04) 5 yr OS: 76 vs. 83 (NS)
MaNGO ILIADE-3 (1998-2007) [29]
157
Stage IIB-IIIC Serous/clear cell histology excluded
PRT vs. PRT+CT(CD)
PFS
5 yr PFS: 61 vs. 74 (NS) 5 yr OS: 73 vs. 78 (NS)
GOG 184 (2000-2004) [41]
552
Optimally debulked Stage III-IV
VD-RT+CD vs. VD-RT+CDP
RFS
3 yr PFS: 62 vs. 64 (NS)
GOG 258 (2009-present)
804
Optimally debulked Stage III-IVa Stage I-II disease-serous or clear cell histology
VD-RT/cisplatin+CP (4 cycles) vs. CP (6 cycles)
RFS
Ongoing study
Stage I-III (high risk profile)
PRT vs. PRT/cisplatin+CP (4 cycles)
OS, FFS
Ongoing study
PORTEC III (2006-present)
PFS, OS
5 yr PFS: 38 vs. 42 (p
