TEXT: Triptorelin With Either Exemestane or Tamoxifen in Treating Premenopausal Women With Hormone-Responsive Breast Cancer

• Sponsor: ETOP IBCSG Partners Foundation (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00066703
• Collaborator: National Cancer Institute (NCI) (NIH), Breast International Group (Other)
• Enrollment: 2,672
• Locations: 228
• Arms: 2
• Duration (Months): 264.9
• Patients Per Site: 11.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using triptorelin, exemestane, and tamoxifen may fight breast cancer by blocking the use of estrogen. It is not yet known whether giving triptorelin together with exemestane is more effective than triptorelin and tamoxifen in treating hormone-responsive breast cancer.

PURPOSE: This randomized phase III trial is studying triptorelin and exemestane to see how well they work compared to triptorelin and tamoxifen in treating premenopausal women with hormone-responsive breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: exemestane; Drug: tamoxifen; Drug: triptorelin	Phase 3

Detailed Description

OBJECTIVES:

• Compare the disease-free survival, breast cancer-free interval, distant recurrence-free interval and overall survival of premenopausal women with endocrine-responsive breast cancer when treated with triptorelin and exemestane vs triptorelin and tamoxifen.

• Compare the quality of life, including late side effects of early menopause, of patients treated with these regimens.

OUTLINE: This is a randomized, international, multicenter study. Patients are stratified according to planned use of concurrent adjuvant chemotherapy (yes vs no), and number of positive lymph nodes (0 vs 1 or more). Treatment duration is 5 years. Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then annually thereafter. Quality of life is assessed at baseline, every 6 months for 2 years, and annually for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2672 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Trial Evaluating The Role Of Exemestane Plus GnRH Analogue As Adjuvant Therapy For Premenopausal Women With Endocrine Responsive Breast Cancer
• Study Start Date: Nov 3, 2003
• Actual Primary Completion Date: Mar 11, 2011
• Anticipated Study Completion Date: Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: T+OFS Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Drug: tamoxifen; Other Names: Nolvadex ; Drug: triptorelin; Other Names: GnRH analogue Trelstar Depot Decapeptyl Depot
Experimental: E+OFS Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Drug: exemestane; Other Names: Aromasin ; Drug: triptorelin; Other Names: GnRH analogue Trelstar Depot Decapeptyl Depot

Outcome Measures

Primary Outcome Measures

1. Disease-free Survival [5-year estimate reported at a median follow-up of 72 months]

   Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow up.

Secondary Outcome Measures

1. Breast Cancer-free Interval [5-year estimate reported at a median follow-up of 72 months]

   Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to the invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up.

2. Distant Recurrence-free Interval [5-year estimates reported at a median follow-up of 72 months]

   Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free interval is defined as the time from randomization to breast cancer recurrence at a distant site; or censored at date of last follow-up

3. Overall Survival [8-year estimates, reported at a median follow-up of 9 years]

   Estimated percentage of patients alive at 8 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed breast cancer

• Completely resected disease

• No clinically detectable residual loco-regional axillary disease

• Prior surgery for primary breast cancer of 1 of the following types:

• Total mastectomy with or without adjuvant radiotherapy

• Breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial mastectomy with margins negative* for invasive disease and ductal carcinoma in situ) with planned radiotherapy NOTE: *If all other margins are clear a positive posterior (deep) margin is permitted, provided the excision was performed down to the pectoral fascia and all tumor has been removed OR a positive anterior (superficial; abutting skin) margin is allowed provided all tumor was removed

• Tumor confined to the breast and axillary nodes

• Tumor detected in internal mammary chain nodes by sentinel node procedure and is not enlarged is allowed

• Axillary lymph node dissection or a negative axillary sentinel node biopsy required

• Patients with negative or microscopically positive axillary sentinel nodes are eligible

• Positive sentinel nodes must have either axillary dissection or radiation of axillary nodes

• No distant metastases

• No locally advanced inoperable breast cancer, including any of the following:

• Inflammatory breast cancer

• Supraclavicular node involvement

• Enlarged internal mammary nodes (unless pathologically negative)

• Bilateral synchronous invasive breast cancer allowed if disease meets all other eligibility criteria

• No prior ipsilateral or contralateral invasive breast cancer

• Hormone receptor status:

• Estrogen and/or progesterone receptor positive

• At least 10% of the tumor cells positive by immunohistochemistry

• If > 1 breast tumor, each tumor must be hormone receptor positive

PATIENT CHARACTERISTICS:

Age

• Premenopausal

Sex

• Female

Menopausal status

• Premenopausal

• Estradiol in the premenopausal range after prior surgery OR meets the following criteria:

• Menstruating regularly for the past 6 months

• Has not used any form of hormonal treatment (including hormonal contraception) within the past 6 months

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• No systemic hepatic disease that would preclude prolonged follow-up

Renal

• No systemic renal disease that would preclude prolonged follow-up

Cardiovascular

• No systemic cardiovascular disease that would preclude prolonged follow-up

• No prior thrombosis (e.g., deep vein thrombosis) and/or embolism unless patient is medically suitable

Pulmonary

• No systemic pulmonary disease that would preclude prolonged follow-up

Other

• Not pregnant or nursing

• Fertile patients must use effective nonhormonal contraception

• No history of noncompliance to medical regimens

• No other nonmalignant systemic disease that would preclude prolonged follow-up

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, nonbreast carcinoma in situ, contralateral or ipsilateral carcinoma in situ of the breast, or other nonrecurrent invasive nonbreast malignancy, including any of the following:

• Stage I papillary thyroid cancer

• Stage IA carcinoma of the cervix

• Stage IA or B endometrioid endometrial cancer

• Borderline or stage I ovarian cancer

• No psychiatric, addictive, or other disorder that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior or concurrent neoadjuvant or adjuvant trastuzumab allowed

Chemotherapy

• No prior neoadjuvant or adjuvant chemotherapy

Endocrine therapy

• No prior tamoxifen, other selective estrogen-receptor modulators (SERMs) (e.g., raloxifene), or hormone replacement therapy for more than 1 year before breast cancer diagnosis

• No prior neoadjuvant or adjuvant endocrine therapy since diagnosis of breast cancer

• No concurrent oral or transdermal hormonal therapy

• No other concurrent estrogen, progesterone, or androgens

• No other concurrent aromatase inhibitors

• No concurrent oral or other hormonal contraceptives (i.e., implants or depot injections)

Radiotherapy

• See Disease Characteristics

• No prior ovarian radiotherapy

Surgery

• See Disease Characteristics

• No prior bilateral oophorectomy

Other

• No concurrent bisphosphonates, except in the following cases:

• Bone density is at least 1.5 standard deviations below the young adult normal mean

• Participation in a randomized clinical study testing bisphosphonates in the adjuvant breast cancer setting

• No other concurrent investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Roy and Patricia Disney Family Cancer Center at Providence Saint Joseph Medical Center	Burbank	California	United States	91505
2	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
3	Providence Holy Cross Cancer Center	Mission Hills	California	United States	91346-9600
4	Desert Regional Medical Center Comprehensive Cancer Center	Palm Springs	California	United States	92262
5	Sutter Cancer Center at Roseville Medical Center	Roseville	California	United States	95661
6	Sutter Cancer Center	Sacramento	California	United States	95816
7	Mercy General Hospital	Sacramento	California	United States	95819
8	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
9	Ruby L. Golleher Cancer Program at Presbyterian Intercommunity Hospital	Whittier	California	United States	90602
10	University of Colorado Cancer Center at UC Health Sciences Center	Aurora	Colorado	United States	80045
11	Shaw Regional Cancer Center	Edwards	Colorado	United States	81632
12	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
13	Front Range Cancer Specialists	Fort Collins	Colorado	United States	80528
14	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center	Farmington	Connecticut	United States	06360-2875
15	Sibley Memorial Hospital	Washington	District of Columbia	United States	20016
16	Walter Reed Army Medical Center	Washington	District of Columbia	United States	20307-5001
17	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
18	Northeast Georgia Medical Center	Gainesville	Georgia	United States	30501
19	Mountain States Tumor Institute at St. Luke's Regional Medical Center	Boise	Idaho	United States	83712
20	Kootenai Cancer Center - Coeur d'Alene	Coeur d'Alene	Idaho	United States	83814
21	Resurrection Medical Center	Chicago	Illinois	United States	60631
22	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
23	Decatur Memorial Hospital Cancer Care Institute	Decatur	Illinois	United States	62526
24	Evanston Hospital	Evanston	Illinois	United States	60201-1781
25	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
26	Elkhart Clinic, LLC	Elkhart	Indiana	United States	46514-2098
27	Elkhart General Hospital	Elkhart	Indiana	United States	46515
28	Fort Wayne Medical Oncology and Hematology	Fort Wayne	Indiana	United States	46845
29	Howard Community Hospital	Kokomo	Indiana	United States	46904
30	Center for Cancer Therapy at LaPorte Hospital and Health Services	La Porte	Indiana	United States	46350
31	Saint Joseph Regional Medical Center	Mishawaka	Indiana	United States	46545-1470
32	CCOP - Northern Indiana CR Consortium	South Bend	Indiana	United States	46601
33	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
34	Michiana Hematology-Oncology, PC - South Bend	South Bend	Indiana	United States	46601
35	South Bend Clinic	South Bend	Indiana	United States	46617
36	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
37	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas	United States	66720
38	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas	United States	67801
39	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas	United States	67042
40	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
41	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas	United States	67068
42	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
43	Cancer Center of Kansas, PA - Newton	Newton	Kansas	United States	67114
44	Menorah Medical Center	Overland Park	Kansas	United States	66209
45	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas	United States	67357
46	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas	United States	67124
47	Cancer Center of Kansas, PA - Salina	Salina	Kansas	United States	67401
48	Shawnee Mission Medical Center	Shawnee Mission	Kansas	United States	66204
49	Cotton-O'Neil Cancer Center	Topeka	Kansas	United States	66606
50	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas	United States	67152
51	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67208
52	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
53	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
54	CCOP - Wichita	Wichita	Kansas	United States	67214
55	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
56	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas	United States	67156
57	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
58	Mercy Medical Center	Baltimore	Maryland	United States	21202
59	Suburban Hospital	Bethesda	Maryland	United States	20814
60	Frederick Memorial Hospital Regional Cancer Therapy Center	Frederick	Maryland	United States	21701
61	Tufts Medical Center Cancer Center	Boston	Massachusetts	United States	02111
62	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
63	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
64	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
65	Bethke Cancer Center at Emerson Hospital	Concord	Massachusetts	United States	01742
66	Addison Gilbert Hospital	Gloucester	Massachusetts	United States	01930
67	Lowell General Hospital	Lowell	Massachusetts	United States	01854
68	NSMC Cancer Center - Peabody	Peabody	Massachusetts	United States	01960
69	MidMichigan Medical Center - Midland	Midland	Michigan	United States	48670
70	William Beaumont Hospital - Royal Oak Campus	Royal Oak	Michigan	United States	48073
71	Lakeland Regional Cancer Care Center - St. Joseph	Saint Joseph	Michigan	United States	49085
72	Lakeside Cancer Specialists, PLLC	Saint Joseph	Michigan	United States	49085
73	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
74	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
75	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
76	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
77	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
78	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
79	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
80	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
81	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
82	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
83	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
84	Regions Hospital Cancer Care Center	Saint Paul	Minnesota	United States	55101
85	United Hospital	Saint Paul	Minnesota	United States	55102
86	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
87	Truman Medical Center - Hospital Hill	Kansas City	Missouri	United States	64108
88	Saint Luke's Cancer Institute at Saint Luke's Hospital	Kansas City	Missouri	United States	64111
89	St. Joseph Medical Center	Kansas City	Missouri	United States	64114
90	North Kansas City Hospital	Kansas City	Missouri	United States	64116
91	CCOP - Kansas City	Kansas City	Missouri	United States	64131
92	Research Medical Center	Kansas City	Missouri	United States	64132
93	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
94	Saint Louis University Cancer Center	Saint Louis	Missouri	United States	63110
95	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
96	Saint Francis Cancer Treatment Center at Saint Francis Memorial Health Center	Grand Island	Nebraska	United States	68803
97	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-6805
98	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey	United States	08053
99	Franklin & Edith Scarpa Regional Cancer Center at South Jersey Healthcare	Vineland	New Jersey	United States	08360
100	Fox Chase Virtua Health Cancer Program at Virtua West Jersey	Voorhees	New Jersey	United States	08043
101	Our Lady of Mercy Medical Center Comprehensive Cancer Center	Bronx	New York	United States	10466
102	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
103	NYU Cancer Institute at New York University Medical Center	New York	New York	United States	10016
104	Randolph Hospital	Asheboro	North Carolina	United States	27203-5400
105	Mission Hospitals - Memorial Campus	Asheville	North Carolina	United States	28801
106	Hope A Women's Cancer Center	Asheville	North Carolina	United States	28816
107	Moses Cone Regional Cancer Center at Wesley Long Community Hospital	Greensboro	North Carolina	United States	27403-1198
108	Pardee Memorial Hospital	Hendersonville	North Carolina	United States	28791
109	Kinston Medical Specialists	Kinston	North Carolina	United States	28501
110	Annie Penn Cancer Center	Reidsville	North Carolina	United States	27320
111	Aultman Cancer Center at Aultman Hospital	Canton	Ohio	United States	44710-1799
112	MetroHealth Cancer Care Center at MetroHealth Medical Center	Cleveland	Ohio	United States	44109
113	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
114	Geisinger Hazleton Cancer Center	Hazleton	Pennsylvania	United States	18201
115	Geisinger Medical Group - Scenery Park	State College	Pennsylvania	United States	16801
116	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
117	CCOP - Greenville	Greenville	South Carolina	United States	29615
118	Medical X-Ray Center, PC	Sioux Falls	South Dakota	United States	57105
119	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
120	Erlanger Cancer Center at Erlanger Hospital - Baroness	Chattanooga	Tennessee	United States	37403
121	West Tennessee Cancer Center at Jackson-Madison County General Hospital	Jackson	Tennessee	United States	38301
122	Doctor's Hospital of Laredo	Laredo	Texas	United States	78041
123	Mountainview Medical	Berlin	Vermont	United States	05602
124	Fletcher Allen Health Care - University Health Center Campus	Burlington	Vermont	United States	05401
125	Madigan Army Medical Center - Tacoma	Tacoma	Washington	United States	98431
126	Mary Babb Randolph Cancer Center at West Virginia University Hospitals	Morgantown	West Virginia	United States	26506
127	Langlade Memorial Hospital	Antigo	Wisconsin	United States	54409
128	Aurora Memorial Hospital of Burlington	Burlington	Wisconsin	United States	53105
129	Oncology Alliance - Franklin	Franklin	Wisconsin	United States	53132
130	Oncology Alliance, SC - Milwaukee - East	Glendale	Wisconsin	United States	53212-1038
131	Oncology Alliance - Kenosha South	Kenosha	Wisconsin	United States	53143
132	Aurora Advanced Healthcare East Mequon Clinic	Mequon	Wisconsin	United States	53092
133	Columbia-Saint Mary's Hospital-Ozaukee	Mequon	Wisconsin	United States	53097
134	Columbia Saint Mary's Water Tower Medical Commons Milwaukee	Mequon	Wisconsin	United States	53211
135	Oncology Alliance, SC - Milwaukee - South	Milwaukee	Wisconsin	United States	53215
136	Aurora Health Center - Racine	Racine	Wisconsin	United States	53406-5661
137	Aurora Health Center - Waukesha	Waukesha	Wisconsin	United States	53188
138	University of Wisconcin Cancer Center at Aspirus Wausau Hospital	Wausau	Wisconsin	United States	54401
139	Oncology Alliance, SC - Milwaukee - West	Wauwatosa	Wisconsin	United States	53226
140	Cancer Therapy Centre at Campbelltown Hospital	Campbelltown	New South Wales	Australia	2560
141	Coffs Harbour Health Campus	Coffs Harbour	New South Wales	Australia	2450
142	Lismore Base Hospital	Lismore	New South Wales	Australia	2480
143	Cancer Therapy Centre at Liverpool Hospital	Liverpool	New South Wales	Australia	2170
144	Tamworth Base Hospital	Tamworth	New South Wales	Australia	2340
145	Manning Base Hospital	Taree	New South Wales	Australia	2430
146	Tweed Heads Hospital	Tweed Heads	New South Wales	Australia	2485
147	Newcastle Mater Misericordiae Hospital	Waratah	New South Wales	Australia	2298
148	Royal Brisbane and Women's Hospital	Brisbane	Queensland	Australia	4029
149	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
150	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
151	Launceston General Hospital	Launceston	Tasmania	Australia	7250
152	Box Hill Hospital	Box Hill	Victoria	Australia	3128
153	Breast Unit Mercy Private	East Melbourne	Victoria	Australia	3002
154	Peter MacCallum Cancer Centre	East Melbourne	Victoria	Australia	3002
155	St. Vincent's Hospital - Melbourne	Fitzroy	Victoria	Australia	3065
156	Austin Hospital	Heidelberg	Victoria	Australia	3084
157	Alfred Hospital	Melbourne	Victoria	Australia	3004
158	Maroondah Hospital	Ringwood East	Victoria	Australia	3135
159	Royal Perth Hospital	Perth	Western Australia	Australia	6000
160	Institut Jules Bordet	Brussels		Belgium	1000
161	Centre Hospitalier Hutois	Huy		Belgium	4500
162	U.Z. Gasthuisberg	Leuven		Belgium	B-3000
163	CHU Liege - Domaine Universitaire du Sart Tilman	Liege		Belgium	B-4000
164	Centre Hospitalier Peltzer-La Tourelle	Verviers		Belgium	B-4800
165	Hospital de Clinicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil	90035-003
166	Tom Baker Cancer Centre - Calgary	Calgary	Alberta	Canada	T2N 4N2
167	Cross Cancer Institute at University of Alberta	Edmonton	Alberta	Canada	T6G 1Z2
168	Doctor Leon Richard Oncology Centre	Moncton	New Brunswick	Canada	E1C 8X3
169	Margaret and Charles Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
170	Trillium Health Centre - Mississauga Site	Toronto	Ontario	Canada	M9C 1A5
171	Windsor Regional Cancer Centre at Windsor Regional Hospital	Windsor	Ontario	Canada	N8W 2X3
172	Hopital Charles Lemoyne	Greenfield Park	Quebec	Canada	J4V 2H1
173	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan	Canada	S4T 7T1
174	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan	Canada	S7N 4H4
175	Cairo Oncology Center	Cairo		Egypt
176	National Cancer Institute of Egypt	Cairo		Egypt
177	Brustzentrum Klinikum Mittelbaden	Baden-Baden		Germany	76532
178	Klinikum Deggendorf	Deggendorf		Germany	94469
179	Frauenklinik des Universitaetsklinikum Erlangen	Erlangen		Germany	91054
180	Universitaetsfrauenklinik Frankfurt	Frankfurt		Germany	D-60596
181	Universitaets-Frauenklinik Goettingen	Göttingen		Germany	D-37075
182	St. Vincentius - Kliniken	Karlsruhe		Germany	D-76137
183	Universitaetsklinikum Schleswig-Holstein - Campus Luebeck	Luebeck		Germany	D-23538
184	Universitatsklinik Mainz	Mainz		Germany	55101
185	Universitaetsfrauenklinik Mannheim	Mannheim		Germany	68167
186	Klinikum Schwaebisch Gmuend Stauferklinik	Mutlangen		Germany	D-73557
187	Klinikum Nuernberg - Klinikum Nord	Nuremberg		Germany	D-90419
188	Caritas - Krankenhaus Saint Josef	Regensburg		Germany	93053
189	Klinikum Obergoeltzsch Rodewisch	Rodewisch		Germany	08228
190	Klinikum Rosenheim	Rosenheim		Germany	83022
191	Klinikum Landkreis Tuttlingen	Tuttlingen		Germany	78532
192	National Institute of Oncology	Budapest		Hungary	1122
193	Tata Memorial Hospital	Mumbai		India	400012
194	Centro di Riferimento Oncologico - Aviano	Aviano		Italy	33081
195	Ospedali Riuniti di Bergamo	Bergamo		Italy	24100
196	Azienda Sanitaria di Bolzano	Bolzano		Italy	39100
197	Spedali Civili di Brescia	Brescia		Italy	25124
198	Ospedale Civile Ramazzini	Carpi		Italy	41012
199	European Institute of Oncology	Milan		Italy	20141
200	Fondazione Salvatore Maugeri	Pavia		Italy	I-27100
201	Misericordia e Dolce Hospital	Prato		Italy	59100
202	Ospedale Civile Rimini	Rimini		Italy	47900
203	Istituto Clinico Humanitas	Rozzano		Italy	20089
204	Policlinico Universitario Udine	Udine		Italy	33100
205	Ospedale di Circolo e Fondazione Macchi	Varese		Italy	21100
206	Waikato Hospital	Hamilton		New Zealand	2020
207	Instituto Nacional de Enfermedades Neoplasicas	Lima		Peru	34
208	Institute of Oncology - Ljubljana	Ljubljana		Slovenia	Sl-1000
209	Sandton Oncology Centre	Johannesburg		South Africa	2121
210	Sahlgrenska University Hospital	Gothenburg		Sweden	S-413 45
211	University Hospital of Linkoping	Linkoping		Sweden	S-581 85
212	Skaraborgs Hospital	Skovde		Sweden	541 85
213	Universitaetsspital-Basel	Basel		Switzerland	CH-4031
214	Oncology Institute of Southern Switzerland	Bellinzona		Switzerland	CH-6500
215	Inselspital Bern	Bern		Switzerland	CH-3010
216	Oncocare Sonnenhof-Klinik Engeriedspital	Bern		Switzerland	CH-3012
217	Kantonsspital Graubuenden	Chur		Switzerland	CH-7000
218	Onkologie-Praxis ZeTup Chur	Chur		Switzerland	CH-7000
219	Centre Hospitalier Universitaire Vaudois	Lausanne		Switzerland	1011
220	Ospedale "la Carita", Locarno	Locarno		Switzerland	6600
221	Ospedale Civico	Lugano		Switzerland	CH-6903
222	Ospedale Beata Vergine	Mendrisio		Switzerland	CH-6850
223	Kantonsspital - St. Gallen	St. Gallen		Switzerland	CH-9007
224	Regionalspital	Thun		Switzerland	3600
225	UniversitaetsSpital Zuerich	Zurich		Switzerland	CH-8091
226	Addenbrooke's Hospital	Cambridge	England	United Kingdom	CB2 2QQ
227	Peterborough Hospitals Trust	Peterborough	England	United Kingdom	PE3 6DA
228	South Tyneside District Hospital	South Shields	England	United Kingdom	NE34 0PL

Sponsors and Collaborators

• ETOP IBCSG Partners Foundation
• National Cancer Institute (NCI)
• Breast International Group

Investigators

• Study Chair: Olivia Pagani, MD, Oncology Institute of Southern Switzerland
• Study Chair: Barbara Walley, MD, FRCPC, Tom Baker Cancer Centre

Study Documents (Full-Text)

None provided.

More Information

Publications

• Francis P, Fleming G, Nasi ML, et al.: Tailored treatment investigations for premenopausal women with endocrine responsive (ER+ and/or PGR+) breast cancer: the SOFT, TEXT, and PERCHE trials. [Abstract] The Breast 12 (Suppl 1): A-P104, S44, 2003.
• Rabaglio M, Ruepp B; Soft/Text/Perche Steering Committee. Death due to liver failure during endocrine therapy for premenopausal breast cancer. Acta Oncol. 2010 Aug;49(6):874-6. doi: 10.3109/0284186X.2010.484813.
• Regan MM, Pagani O, Fleming GF, Walley BA, Price KN, Rabaglio M, Maibach R, Ruepp B, Coates AS, Goldhirsch A, Colleoni M, Gelber RD, Francis PA; International Breast Cancer Study; GroupSOFT and TEXT Investigators. Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: design of the TEXT and SOFT trials. Breast. 2013 Dec;22(6):1094-100. doi: 10.1016/j.breast.2013.08.009. Epub 2013 Oct 2.
• Regan MM, Pagani O, Walley B, Torrisi R, Perez EA, Francis P, Fleming GF, Price KN, Thürlimann B, Maibach R, Castiglione-Gertsch M, Coates AS, Goldhirsch A, Gelber RD; SOFT/TEXT/PERCHE Steering Committee and the International Breast Cancer Study Group. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy? Ann Oncol. 2008 Jul;19(7):1231-1241. doi: 10.1093/annonc/mdn037. Epub 2008 Mar 5.

• Responsible Party: ETOP IBCSG Partners Foundation
• ClinicalTrials.gov Identifier: NCT00066703
• Other Study ID Numbers: IBCSG 25-02 / BIG 3-02; IBCSG 25-02; BIG 3-02; NABCI IBCSG 25-02; EU-20347; 2004-000168-28; CDR0000316458
• First Posted: Aug 7, 2003
• Last Update Posted: Mar 11, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by ETOP IBCSG Partners Foundation: stage II breast cancer; stage IIIA breast cancer; estrogen receptor-positive breast cancer; progesterone receptor-positive breast cancer; stage IA breast cancer; stage IB breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Tamoxifen; Triptorelin Pamoate; Exemestane

Study Results

Participant Flow

Recruitment Details	2672 patients were randomized between 7Nov03 and 7Apr11 at 182 centers in 15 countries.

Arm/Group Title	T+OFS	E+OFS
Arm/Group Description	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
Period Title: Overall Study
STARTED	1334	1338
COMPLETED	722	756
NOT COMPLETED	612	582

Baseline Characteristics

Arm/Group Title	T+OFS	E+OFS	Total
Arm/Group Description	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Total of all reporting groups
Overall Participants	1328	1332	2660
Age (years) [Median (Inter-Quartile Range) ]
Age	44	43	43
Sex: Female, Male (Count of Participants)
Female	1328 100%	1332 100%	2660 100%
Male	0 0%	0 0%	0 0%
Lymph-node status (percent of participants) [Number]
Negative	52 3.9%	52 3.9%	104 3.9%
Positive	48 3.6%	48 3.6%	96 3.6%
Tumor size (percent of participants) [Number]
<=2 cm	60 4.5%	59 4.4%	119 4.5%
>=2 cm	39 2.9%	40 3%	79 3%
unknown	1 0.1%	1 0.1%	2 0.1%
Tumor grade (percent of participants) [Number]
1	17 1.3%	17 1.3%	34 1.3%
2	56 4.2%	55 4.1%	111 4.2%
3	26 2%	27 2%	53 2%
unknown	1 0.1%	1 0.1%	2 0.1%
HER2 status (percent of participants) [Number]
Negative	87 6.6%	87 6.5%	174 6.5%
Positive	12 0.9%	12 0.9%	24 0.9%
Unknown	1 0.1%	1 0.1%	2 0.1%

Outcome Measures

1. Primary Outcome

Title	Disease-free Survival
Description	Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow up.
Time Frame	5-year estimate reported at a median follow-up of 72 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	T+OFS	E+OFS
Arm/Group Description	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
Measure Participants	1328	1332
Number (95% Confidence Interval) [percentage of participants]	87.3 6.6%	91.1 6.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+OFS, E+OFS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.0002
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.717
	Confidence Interval	(2-Sided) 95%; 0.602 to 0.855
	Parameter Dispersion	Type: Value:
	Estimation Comments	T+OFS is the reference group in the estimation of the hazard ratio.

2. Secondary Outcome

Title	Breast Cancer-free Interval
Description	Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to the invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up.
Time Frame	5-year estimate reported at a median follow-up of 72 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	T+OFS	E+OFS
Arm/Group Description	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
Measure Participants	1328	1332
Number (95% Confidence Interval) [percentage of participants]	88.8 6.7%	92.8 7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+OFS, E+OFS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.664
	Confidence Interval	(2-Sided) 95%; .548 to .804
	Parameter Dispersion	Type: Value:
	Estimation Comments	T+OFS is the reference group for the estimation of the hazard ratio.

3. Secondary Outcome

Title	Distant Recurrence-free Interval
Description	Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free interval is defined as the time from randomization to breast cancer recurrence at a distant site; or censored at date of last follow-up
Time Frame	5-year estimates reported at a median follow-up of 72 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	T+OFS	E+OFS
Arm/Group Description	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
Measure Participants	1328	1332
Number (95% Confidence Interval) [percentage of participants]	92.0 6.9%	93.8 7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+OFS, E+OFS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.777
	Confidence Interval	(2-Sided) 95%; 0.624 to 0.967
	Parameter Dispersion	Type: Value:
	Estimation Comments	T+OFS was the reference group in the estimation of the hazard ratio

4. Secondary Outcome

Title	Overall Survival
Description	Estimated percentage of patients alive at 8 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive.
Time Frame	8-year estimates, reported at a median follow-up of 9 years

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	T+OFS	E+OFS
Arm/Group Description	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
Measure Participants	1328	1332
Number (95% Confidence Interval) [percentage of participants]	93.3 7%	93.4 7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T+OFS, E+OFS
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	T+OFS was the reference group in the estimation of the hazard ratio

Adverse Events

Time Frame	Assessed every 3 months for the first year, then every 6 months until year 6. Reported at a median follow-up of 72 months.
Adverse Event Reporting Description	Targeted adverse events and other grade 3 or higher adverse events were collected on CRFs, regardless of attribution. The safety population EXCLUDES patients who never started protocol-assigned therapy.
Arm/Group Title	T+OFS		E+OFS
Arm/Group Description	Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.		Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin.
All Cause Mortality
	T+OFS		E+OFS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	T+OFS		E+OFS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	484/1321 (36.6%)		496/1317 (37.7%)
Blood and lymphatic system disorders
Hemolysis (e.g., immune hemolytic anemia, drug related hemolysis, other)	1/1321 (0.1%)		0/1317 (0%)
Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura or hemolytic uremic syndrome)	1/1321 (0.1%)		0/1317 (0%)
Blood/Bone Marrow-Other (Specify)	0/1321 (0%)		1/1317 (0.1%)
Febrile neutropenia	1/1321 (0.1%)		1/1317 (0.1%)
Hemoglobin	3/1321 (0.2%)		2/1317 (0.2%)
Cardiac disorders
Cardiac Arrhythmia-Other (Specify)	1/1321 (0.1%)		0/1317 (0%)
Cardiac-ischemia/infarction	2/1321 (0.2%)		4/1317 (0.3%)
Left ventricular diastolic dysfunction	0/1321 (0%)		1/1317 (0.1%)
Left ventricular systolic dysfunction	3/1321 (0.2%)		1/1317 (0.1%)
Pain - Cardiac/heart	0/1321 (0%)		1/1317 (0.1%)
Supraventricular and nodal arrhythmia - Atrial fibrillation	2/1321 (0.2%)		2/1317 (0.2%)
Supraventricular and nodal arrhythmia - Sinus tachycardia	2/1321 (0.2%)		0/1317 (0%)
Supraventricular and nodal arrhythmia - Supraventricular arrhythmia NOS	1/1321 (0.1%)		0/1317 (0%)
Supraventricular and nodal arrhythmia - Supraventricular tachycardia	0/1321 (0%)		1/1317 (0.1%)
Valvular heart disease	0/1321 (0%)		1/1317 (0.1%)
Ear and labyrinth disorders
Auditory/Ear-Other (Specify)	1/1321 (0.1%)		1/1317 (0.1%)
Endocrine disorders
Thyroid function, high (hyperthyroidism, thyrotoxicosis)	2/1321 (0.2%)		0/1317 (0%)
Thyroid function, low (hypothyroidism)	1/1321 (0.1%)		1/1317 (0.1%)
Endocrine-Other (Specify)	1/1321 (0.1%)		1/1317 (0.1%)
Eye disorders
Cataract	1/1321 (0.1%)		1/1317 (0.1%)
Retinal detachment	1/1321 (0.1%)		1/1317 (0.1%)
Retinopathy	1/1321 (0.1%)		0/1317 (0%)
Gastrointestinal disorders
Hemorrhage, GI - Rectum	1/1321 (0.1%)		1/1317 (0.1%)
Hemorrhage, GI - Varices (rectal)	1/1321 (0.1%)		0/1317 (0%)
Obstruction, GI - Small bowel NOS	0/1321 (0%)		1/1317 (0.1%)
Perforation, GI - Duodenum	1/1321 (0.1%)		0/1317 (0%)
Stricture/stenosis (including anastomotic), GI - Esophagus	1/1321 (0.1%)		0/1317 (0%)
Ulcer, GI - Stomach	0/1321 (0%)		1/1317 (0.1%)
Colitis	1/1321 (0.1%)		0/1317 (0%)
Constipation	2/1321 (0.2%)		0/1317 (0%)
Diarrhea	3/1321 (0.2%)		1/1317 (0.1%)
Gastritis (including bile reflux gastritis)	0/1321 (0%)		2/1317 (0.2%)
Gastrointestinal-Other (Specify)	1/1321 (0.1%)		3/1317 (0.2%)
Hemorrhoids	2/1321 (0.2%)		0/1317 (0%)
Nausea	9/1321 (0.7%)		15/1317 (1.1%)
Pain - Abdomen NOS	5/1321 (0.4%)		3/1317 (0.2%)
Pain - Stomach	0/1321 (0%)		2/1317 (0.2%)
Pancreatitis	1/1321 (0.1%)		0/1317 (0%)
Vomiting	1/1321 (0.1%)		1/1317 (0.1%)
General disorders
Fatigue (asthenia, lethargy, malaise)	32/1321 (2.4%)		41/1317 (3.1%)
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	1/1321 (0.1%)		0/1317 (0%)
Death not associated with CTCAE term - Sudden death	1/1321 (0.1%)		0/1317 (0%)
Flu-like syndrome	1/1321 (0.1%)		0/1317 (0%)
Injection site reaction/extravasation changes	1/1321 (0.1%)		0/1317 (0%)
Pain - Chest/thorax NOS	0/1321 (0%)		4/1317 (0.3%)
Pain-Other (Specify)	2/1321 (0.2%)		0/1317 (0%)
Hepatobiliary disorders
Obstruction, GI - Gallbladder	2/1321 (0.2%)		0/1317 (0%)
Cholecystitis	5/1321 (0.4%)		1/1317 (0.1%)
Hepatobiliary/Pancreas-Other (Specify)	5/1321 (0.4%)		1/1317 (0.1%)
Liver dysfunction/failure (clinical)	5/1321 (0.4%)		1/1317 (0.1%)
Pain - Gallbladder	0/1321 (0%)		1/1317 (0.1%)
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	7/1321 (0.5%)		5/1317 (0.4%)
Allergy/Immunology-Other (Specify)	0/1321 (0%)		1/1317 (0.1%)
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils - Foreign body (e.g., graft, implant)	4/1321 (0.3%)		0/1317 (0%)
Infection with unknown ANC - Foreign body (e.g., graft, implant, prosthesis, stent)	1/1321 (0.1%)		0/1317 (0%)
Infection (documented clinically or microbiologically) w/Grade 3 or 4 neutrophils -Catheter-related	0/1321 (0%)		1/1317 (0.1%)
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils - Wound	0/1321 (0%)		1/1317 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Appendix	1/1321 (0.1%)		2/1317 (0.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Bronchus	1/1321 (0.1%)		2/1317 (0.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Catheter-related	0/1321 (0%)		2/1317 (0.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Joint	0/1321 (0%)		1/1317 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Kidney	0/1321 (0%)		1/1317 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Lung (pneumonia)	5/1321 (0.4%)		2/1317 (0.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Middle ear (otitis media)	0/1321 (0%)		1/1317 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Nerve-peripheral	1/1321 (0.1%)		0/1317 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Pelvis NOS	0/1321 (0%)		1/1317 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Salivary gland	0/1321 (0%)		1/1317 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Sinus	1/1321 (0.1%)		1/1317 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Skin (cellulitis)	8/1321 (0.6%)		9/1317 (0.7%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Small bowel NOS	1/1321 (0.1%)		0/1317 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Soft tissue NOS	0/1321 (0%)		2/1317 (0.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Stomach	1/1321 (0.1%)		0/1317 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Upper airway NOS	0/1321 (0%)		2/1317 (0.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Urinary tract NOS	0/1321 (0%)		1/1317 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Wound	0/1321 (0%)		2/1317 (0.2%)
Infection with unknown ANC - Appendix	1/1321 (0.1%)		1/1317 (0.1%)
Infection with unknown ANC - Bronchus	0/1321 (0%)		1/1317 (0.1%)
Infection with unknown ANC - Lung (pneumonia)	2/1321 (0.2%)		0/1317 (0%)
Infection with unknown ANC - Skin (cellulitis)	2/1321 (0.2%)		4/1317 (0.3%)
Infection-Other (Specify)	4/1321 (0.3%)		2/1317 (0.2%)
Injury, poisoning and procedural complications
Wound complication, non-infectious	1/1321 (0.1%)		0/1317 (0%)
Fracture	11/1321 (0.8%)		18/1317 (1.4%)
Intra-operative injury - Ureter	0/1321 (0%)		1/1317 (0.1%)
Intra-operative injury - Vagina	0/1321 (0%)		1/1317 (0.1%)
Thrombosis/embolism (vascular access-related)	29/1321 (2.2%)		13/1317 (1%)
Vessel injury-vein - Extremity-upper	0/1321 (0%)		1/1317 (0.1%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	6/1321 (0.5%)		3/1317 (0.2%)
AST, SGOT (serum glutamic oxaloacetic transaminase)	6/1321 (0.5%)		4/1317 (0.3%)
Cholesterol, serum-high (hypercholesterolemia)	0/1321 (0%)		1/1317 (0.1%)
Bilirubin (hyperbilirubinemia)	0/1321 (0%)		1/1317 (0.1%)
Carbon monoxide diffusion capacity (DL(co))	1/1321 (0.1%)		0/1317 (0%)
GGT (gamma-glutamyl transpeptidase)	2/1321 (0.2%)		4/1317 (0.3%)
INR (International Normalized Ratio of prothrombin time)	0/1321 (0%)		1/1317 (0.1%)
Leukocytes (total WBC)	0/1321 (0%)		3/1317 (0.2%)
Neutrophils/granulocytes (ANC/AGC)	2/1321 (0.2%)		2/1317 (0.2%)
Weight loss	1/1321 (0.1%)		2/1317 (0.2%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	0/1321 (0%)		1/1317 (0.1%)
Calcium, serum-low (hypocalcemia)	0/1321 (0%)		1/1317 (0.1%)
Glucose, serum-high (hyperglycemia)	8/1321 (0.6%)		8/1317 (0.6%)
Phosphate, serum-low (hypophosphatemia)	0/1321 (0%)		1/1317 (0.1%)
Potassium, serum-low (hypokalemia)	0/1321 (0%)		1/1317 (0.1%)
Sodium, serum-low (hyponatremia)	0/1321 (0%)		1/1317 (0.1%)
Triglyceride, serum-high (hypertriglyceridemia)	0/1321 (0%)		1/1317 (0.1%)
Dehydration	2/1321 (0.2%)		1/1317 (0.1%)
Pancreatic endocrine: glucose intolerance	5/1321 (0.4%)		8/1317 (0.6%)
Musculoskeletal and connective tissue disorders
Extremity-upper (function)	0/1321 (0%)		1/1317 (0.1%)
Joint-function	1/1321 (0.1%)		1/1317 (0.1%)
Lymphedema-related fibrosis	0/1321 (0%)		1/1317 (0.1%)
Musculoskeletal/Soft Tissue-Other (Specify)	3/1321 (0.2%)		1/1317 (0.1%)
Osteoporosis	4/1321 (0.3%)		8/1317 (0.6%)
Pain - Back	2/1321 (0.2%)		0/1317 (0%)
Pain - Bone	1/1321 (0.1%)		1/1317 (0.1%)
Pain - Chest wall	1/1321 (0.1%)		1/1317 (0.1%)
Pain - Extremity-limb	1/1321 (0.1%)		0/1317 (0%)
Pain - Joint	69/1321 (5.2%)		139/1317 (10.6%)
Pain - Neck	1/1321 (0.1%)		1/1317 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy-possibly related to cancer treatment (Specify)	0/1321 (0%)		1/1317 (0.1%)
Nervous system disorders
Hemorrhage, CNS	1/1321 (0.1%)		1/1317 (0.1%)
CNS cerebrovascular ischemia	9/1321 (0.7%)		2/1317 (0.2%)
Dizziness	2/1321 (0.2%)		3/1317 (0.2%)
Memory impairment	1/1321 (0.1%)		1/1317 (0.1%)
Neurology-Other (Specify)	2/1321 (0.2%)		4/1317 (0.3%)
Neuropathy: cranial - CN V Motor-jaw muscles; Sensory-facial	2/1321 (0.2%)		0/1317 (0%)
Neuropathy: motor	0/1321 (0%)		2/1317 (0.2%)
Neuropathy: sensory	1/1321 (0.1%)		0/1317 (0%)
Pain - Head/headache	9/1321 (0.7%)		11/1317 (0.8%)
Pain - Neuralgia/peripheral nerve	2/1321 (0.2%)		12/1317 (0.9%)
Seizure	1/1321 (0.1%)		1/1317 (0.1%)
Syncope (fainting)	1/1321 (0.1%)		4/1317 (0.3%)
Vasovagal episode	0/1321 (0%)		1/1317 (0.1%)
Psychiatric disorders
Insomnia	54/1321 (4.1%)		44/1317 (3.3%)
Mood alteration - anxiety	1/1321 (0.1%)		3/1317 (0.2%)
Mood alteration - depression	59/1321 (4.5%)		51/1317 (3.9%)
Psychosis (hallucinations/delusions)	0/1321 (0%)		1/1317 (0.1%)
Renal and urinary disorders
Incontinence, urinary	3/1321 (0.2%)		2/1317 (0.2%)
Obstruction, GU - Ureter	0/1321 (0%)		1/1317 (0.1%)
Cystitis	1/1321 (0.1%)		0/1317 (0%)
Renal/Genitourinary-Other (Specify)	24/1321 (1.8%)		7/1317 (0.5%)
Reproductive system and breast disorders
Hemorrhage, GU - Uterus	0/1321 (0%)		1/1317 (0.1%)
Hemorrhage, GU - Vagina	4/1321 (0.3%)		1/1317 (0.1%)
Breast nipple/areolar deformity	0/1321 (0%)		1/1317 (0.1%)
Irregular menses (change from baseline)	0/1321 (0%)		1/1317 (0.1%)
Pain - Vagina	11/1321 (0.8%)		33/1317 (2.5%)
Sexual/Reproductive Function-Other (Specify)	3/1321 (0.2%)		1/1317 (0.1%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm, wheezing	2/1321 (0.2%)		0/1317 (0%)
Hemorrhage, pulmonary/upper respiratory - Bronchopulmonary NOS	1/1321 (0.1%)		0/1317 (0%)
Apnea	1/1321 (0.1%)		0/1317 (0%)
Cough	0/1321 (0%)		1/1317 (0.1%)
Dyspnea (shortness of breath)	1/1321 (0.1%)		2/1317 (0.2%)
Obstruction/stenosis of airway - Larynx	1/1321 (0.1%)		0/1317 (0%)
Pleural effusion (non-malignant)	1/1321 (0.1%)		0/1317 (0%)
Pneumonitis/pulmonary infiltrates	1/1321 (0.1%)		1/1317 (0.1%)
Pneumothorax	1/1321 (0.1%)		1/1317 (0.1%)
Pulmonary/Upper Respiratory-Other (Specify)	2/1321 (0.2%)		2/1317 (0.2%)
Skin and subcutaneous tissue disorders
Pruritus/itching	1/1321 (0.1%)		1/1317 (0.1%)
Rash/desquamation	1/1321 (0.1%)		0/1317 (0%)
Skin breakdown/decubitus ulcer	1/1321 (0.1%)		0/1317 (0%)
Vascular disorders
Hematoma	0/1321 (0%)		1/1317 (0.1%)
Hot flashes/flushes	149/1321 (11.3%)		127/1317 (9.6%)
Hypertension	100/1321 (7.6%)		90/1317 (6.8%)
Hypotension	1/1321 (0.1%)		0/1317 (0%)
Vascular-Other (Specify)	1/1321 (0.1%)		0/1317 (0%)
Vasculitis	0/1321 (0%)		1/1317 (0.1%)
Other (Not Including Serious) Adverse Events
	T+OFS		E+OFS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1293/1321 (97.9%)		1298/1317 (98.6%)
Cardiac disorders
Cardiac-ischemia/infarction	2/1321 (0.2%)		4/1317 (0.3%)
Gastrointestinal disorders
Nausea	446/1321 (33.8%)		478/1317 (36.3%)
General disorders
Fatigue (asthenia, lethargy, malaise)	807/1321 (61.1%)		760/1317 (57.7%)
Injection site reaction/extravasation changes	99/1321 (7.5%)		86/1317 (6.5%)
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	56/1321 (4.2%)		60/1317 (4.6%)
Injury, poisoning and procedural complications
Fracture	57/1321 (4.3%)		82/1317 (6.2%)
Thrombosis/embolism (vascular access-related)	3/1321 (0.2%)		3/1317 (0.2%)
Metabolism and nutrition disorders
Glucose, serum-high (hyperglycemia)	30/1321 (2.3%)		31/1317 (2.4%)
Pancreatic endocrine: glucose intolerance	16/1321 (1.2%)		17/1317 (1.3%)
Musculoskeletal and connective tissue disorders
Osteoporosis	388/1321 (29.4%)		588/1317 (44.6%)
Pain - Joint	953/1321 (72.1%)		1030/1317 (78.2%)
Nervous system disorders
Hemorrhage, CNS	12/1321 (0.9%)		7/1317 (0.5%)
CNS cerebrovascular ischemia	2/1321 (0.2%)		1/1317 (0.1%)
Psychiatric disorders
Insomnia	738/1321 (55.9%)		714/1317 (54.2%)
Libido	486/1321 (36.8%)		555/1317 (42.1%)
Mood alteration - depression	592/1321 (44.8%)		610/1317 (46.3%)
Renal and urinary disorders
Incontinence, urinary	232/1321 (17.6%)		182/1317 (13.8%)
Reproductive system and breast disorders
Pain - Vagina	336/1321 (25.4%)		374/1317 (28.4%)
Vaginal dryness	611/1321 (46.3%)		683/1317 (51.9%)
Skin and subcutaneous tissue disorders
Sweating (diaphoresis)	752/1321 (56.9%)		705/1317 (53.5%)
Vascular disorders
Hot flashes/flushes	1081/1321 (81.8%)		1076/1317 (81.7%)
Hypertension	179/1321 (13.6%)		213/1317 (16.2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.