Whole-Brain Radiation Therapy or Stereotactic Radiosurgery With or Without Lapatinib Ditosylate in Treating Patients With Brain Metastasis From HER2-Positive Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01622868
• Collaborator: NRG Oncology (Other)
• Enrollment: 143
• Locations: 302
• Arms: 2
• Actual Duration (Months): 117.8
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well whole-brain radiation therapy or stereotactic radiosurgery with or without lapatinib ditosylate works in treating patients with breast cancer that has too many of a protein called human epidermal growth factor receptor 2 (HER2) on its cells and has spread to the brain. Radiation therapy uses high energy x rays to kill tumor cells and shrink tumors. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may kill more tumor cells and cause less damage to normal tissue. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether whole-brain radiation therapy or stereotactic radiosurgery together with lapatinib ditosylate is an effective treatment for brain metastasis from breast cancer.

Condition or Disease	Intervention/Treatment	Phase
HER2-Positive Breast Carcinoma; Invasive Breast Carcinoma; Metastatic Malignant Neoplasm in the Brain; Recurrent Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7	Other: Laboratory Biomarker Analysis; Drug: Lapatinib Ditosylate; Radiation: Stereotactic Radiosurgery; Radiation: Whole-Brain Radiotherapy	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine if there is a signal for an increase in complete response (CR) rate in the measurable brain metastases at 12 weeks post radiation therapy (RT) (whole brain or stereotactic radiosurgery [SRS]) as determined by magnetic-resonance imaging (MRI) scan of the brain, with the addition of lapatinib (lapatinib ditosylate) to whole-brain radiation therapy (WBRT)/SRS compared to WBRT/SRS alone.

SECONDARY OBJECTIVES:

1. To evaluate CR rate of the measurable brain metastases at 4 weeks post RT (WBRT/SRS) as determined by MRI scan of the brain, with the addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

2. To evaluate objective response rate of measurable brain metastases at 4 and 12 weeks post RT (WBRT/SRS) as determined by MRI scan of the brain, with the addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

3. To evaluate targeted lesion-specific objective response rate (CR + partial response [PR]) at 4 and 12 weeks post WBRT/SRS.

4. To evaluate central nervous system (CNS) progressive disease outside the targeted measurable disease with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

5. To evaluate targeted lesion-specific progression at 4 and 12 weeks post WBRT/SRS.

6. To evaluate treatment related adverse events when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

7. To evaluate overall CNS complete response: disappearance of all CNS target lesions sustained for at least 4 weeks; with no new lesions, no use of corticosteroids, and patient is stable or improved clinically, when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

8. To evaluate overall CNS progressive disease (within or outside targeted measurable disease) with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

9. To evaluate overall survival when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments or SRS for 1 treatment.

ARM B: Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate orally (PO) once daily (QD) for 6 weeks.

After completion of study treatment, patients are followed up at 4 and 12 weeks and then every 12 weeks thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 143 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Randomized Study of Whole Brain Radiotherapy/Stereotactic Radiosurgery in Combination With Concurrent Lapatinib in Patients With Brain Metastasis From HER2-Positive Breast Cancer - A Collaborative Study of NRG Oncology and KROG
• Actual Study Start Date: Jul 26, 2012
• Actual Primary Completion Date: Dec 30, 2019
• Actual Study Completion Date: May 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (WBRT or SRS) Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments, or SRS for 1 treatment.	Other: Laboratory Biomarker Analysis; Correlative studies; Radiation: Stereotactic Radiosurgery; Undergo SRS; Other Names: Stereotactic External Beam Irradiation stereotactic external-beam radiation therapy Stereotactic Radiation Therapy Stereotactic Radiotherapy stereotaxic radiation therapy stereotaxic radiosurgery ; Radiation: Whole-Brain Radiotherapy; Undergo WBRT; Other Names: WBRT whole-brain radiation therapy
Experimental: Arm B (lapatinib ditosylate, WBRT or SRS) Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate PO QD for 6 weeks.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Lapatinib Ditosylate; Given PO; Other Names: Tykerb ; Radiation: Stereotactic Radiosurgery; Undergo SRS; Other Names: Stereotactic External Beam Irradiation stereotactic external-beam radiation therapy Stereotactic Radiation Therapy Stereotactic Radiotherapy stereotaxic radiation therapy stereotaxic radiosurgery ; Radiation: Whole-Brain Radiotherapy; Undergo WBRT; Other Names: WBRT whole-brain radiation therapy

Outcome Measures

Primary Outcome Measures

1. Complete Response (CR) Rate in the Brain at 12 Weeks Post-radiation Therapy (RT) Using the RECIST 1.1 Criteria Based on Brain Magnetic Resonance Imaging (MRI) [Baseline and 12 weeks post RT (approximately 12 weeks from start of treatment if SRS and 15 if WBRT)]

   The Response Evaluation Criteria in Solid Tumors (RECIST) criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.

Secondary Outcome Measures

1. Complete Response Rate in the Brain at 4 Weeks Post-RT Using the RECIST 1.1 Criteria Based on Brain MRI [Baseline and 4 weeks post RT (approximately 4 weeks from start of treatment if SRS and 7 if WBRT)]

   The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.

2. Complete Response Rate in the Brain Using the World Health Organization (WHO)/Modified McDonald Criteria Based on Brain MRI [Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)]

   The WHO/modified McDonald Criteria evaluates changes in bidimensional tumor measurements. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.

3. Objective Response Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI [Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)]

   The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Objective response is defined as a complete or partial response. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Partial response is defined as ≥ 30% reduction in the sum of diameters of up to 2 of the largest target lesions. Rate is calculated by dividing the number of patients with objective response by the number of analyzable patients.

4. Percentage of Participants With Progression in the Brain Outside the Targeted Measurable Disease Using the RECIST 1.1 Criteria Based on Brain MRI [From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.]

   The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. CNS progressive disease outside the targeted measureable disease was determined by a retrospective central review of MRI scans by the study neuroradiology co-chair and is defined as the first occurrence since baseline of new lesions or progression of non-target lesions. Time to CNS progressive disease is defined as time from randomization to the date of progressive disease, last known follow-up (censored), or death (competing risk). Progression rates are estimated using the cumulative incidence method. One-year rates are provided.

5. Targeted Lesion-specific Objective Response Rate Using the RECIST 1.1 Measurement Criteria Based on Brain MRI [Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)]

   The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Objective response is defined as a complete or partial response. Complete response is defined as the complete disappearance of all enhancing disease and partial response is defined as ≥ 30% reduction in the diameter of the target lesion. Lesions were evaluated individually. Rate is calculated by dividing the number of lesions with objective response by the number of analyzable lesions.

6. Targeted Lesion-specific Progression Rate Using the RECIST 1.1 Measurement Criteria Based on Brain MRI [Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)]

   The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Progression is defined as ≥ 20% increase in the diameter of the target lesion relative to nadir. Lesions were evaluated individually. Rate is calculated by dividing the number of lesions with progression by the number of analyzable lesions.

7. Frequency of Highest Treatment-related Adverse Event Per Participant [From randomization to last follow-up. Maximum follow-up at time of analysis was 71.6 months.]

   Adverse events reported as definitely, probably, or possibly related to protocol treatment. Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data provided in this outcome measure. See Adverse Events Module for specific Adverse Event data.

8. Overall Complete Response Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI [From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.]

   The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Overall complete response is defined as the complete disappearance of all CNS target lesions sustained for at least 4 weeks; with no new lesions, no use of corticosteroids, and patient is stable or improved clinically. All site-reported MRI data and all site-reporting of clinical progressive disease indicators were used in this analysis. Rate is calculated by dividing the number of participants with overall complete response by the number of analyzable participants.

9. Overall Progression Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI [From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.]

   The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Overall progression is defined as unequivocal progression, new or worsening tumor-related neurological symptoms, tumor-related increase in steroid dose, new primary in brain, or progression in target lesions. All site-reported MRI data and all site-reporting of clinical progressive disease indicators were used in this analysis. Rate is calculated by dividing the number of participants with progression by the number of analyzable participants.

10. Overall Survival (OS) [From randomization to last follow-up. Maximum follow-up at time of analysis was 71.6 months.]

    An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. Analysis occurred after 101 deaths were reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of invasive breast cancer

• HER2-overexpressing breast cancer (3+ staining by immunohistochemistry or HER2 gene amplification by fluorescent in situ hybridization [FISH] or silver in situ hybridization [SISH] >= 2.0)

• At least 1 measurable unirradiated parenchymal brain metastasis within 21 days prior to study entry; patients who are to undergo SRS must have no more than 10 brain metastases; there is no limit on number of brain metastases for WBRT; the minimum size as measured on T1-weighted gadolinium-enhanced MRI must be as follows according to the number of brain metastases:

• For a single solitary lesion the size must be >= 10 mm

• For 2 or more lesions, the size of at least 2 of the lesions must be >= 5 mm

• Patients may also have the following provided the size requirements above are met:

• Progressive parenchymal brain metastasis following stereotactic radiosurgery for 1-3 brain metastases, with at least 1 new measurable brain lesion

• Progressive parenchymal brain metastasis following surgical resection of 1-3 brain metastases, with at least 1 measurable brain lesion

• History/physical examination within 21 days prior to study entry

• Karnofsky performance status >= 60 within 21 days prior to study entry

• Able to swallow and retain oral medication (note: for patients unable to swallow tablets, an oral suspension preparation is acceptable)

• Absolute neutrophil count (ANC) >= 1,200 cells/mm^3 (within 21 days prior to study entry)

• Platelets >= 70,000 cells/mm^3 (within 21 days prior to study entry)

• Hemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dL is acceptable) (within 21 days prior to study entry)

• Creatinine < 1.5 times institutional upper limit of normal (within 21 days prior to study entry)

• Bilirubin < 1.5 times institutional upper limit of normal (within 21 days prior to study entry)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 times institutional upper limit of normal with or without liver metastasis (within 21 days prior to study entry)

• Patient must provide study specific informed consent prior to study entry

• Women of childbearing potential must have a negative serum pregnancy test within 21 days prior to study entry

• Sexually active women of childbearing potential and sexually active men must practice adequate contraception during therapy and for 12 months after protocol treatment completion

• Prior lapatinib is allowed as long as the last dose received was > 21 days prior to study entry and provided the patient has not received it at any time after the diagnosis of brain metastasis

Exclusion Criteria:

• Prior WBRT

• Prior radiation therapy (RT) (any site) with concurrent lapatinib defined as 1 or more days on which the patient received both radiation therapy and lapatinib on the same day

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Prior invasive malignancy (except non-melanomatous skin cancer, curatively resected thyroid papillary carcinoma, and invasive and non-invasive cancers related to the breast cancer) unless disease free for a minimum of 3 years

• Leptomeningeal disease

• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields except patients who have progressed following stereotactic radiosurgery for 1-3 brain metastases, with at least one new lesion

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of study entry

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; hepatic or biliary disease that is acute or currently active or that requires antiviral therapy (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment)

• History of left ventricular ejection fraction (LVEF) below institutional normal unless repeated and within institutional normal range within 90 days of study entry

• Grade 2 or greater rash of any cause at time of study entry

• Grade 2 or greater diarrhea of any cause at time of study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	The Kirklin Clinic at Acton Road	Birmingham	Alabama	United States	35243
3	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama	United States	36688
4	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona	United States	85013
5	Banner University Medical Center - Tucson	Tucson	Arizona	United States	85719
6	Sutter Auburn Faith Hospital	Auburn	California	United States	95602
7	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California	United States	95603
8	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California	United States	94704
9	Mills-Peninsula Medical Center	Burlingame	California	United States	94010
10	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California	United States	95682
11	Mercy San Juan Medical Center	Carmichael	California	United States	95608
12	Sutter Davis Hospital	Davis	California	United States	95616
13	Epic Care-Dublin	Dublin	California	United States	94568
14	Bay Area Breast Surgeons Inc	Emeryville	California	United States	94608
15	Epic Care Partners in Cancer Care	Emeryville	California	United States	94608
16	Contra Costa Regional Medical Center	Martinez	California	United States	94553-3156
17	Memorial Medical Center	Modesto	California	United States	95355
18	Palo Alto Medical Foundation-Camino Division	Mountain View	California	United States	94040
19	Palo Alto Medical Foundation-Gynecologic Oncology	Mountain View	California	United States	94040
20	Sutter Cancer Research Consortium	Novato	California	United States	94945
21	Alta Bates Summit Medical Center - Summit Campus	Oakland	California	United States	94609
22	Bay Area Tumor Institute	Oakland	California	United States	94609
23	Palo Alto Medical Foundation Health Care	Palo Alto	California	United States	94301
24	Stanford Cancer Institute Palo Alto	Palo Alto	California	United States	94304
25	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California	United States	95661
26	Sutter Roseville Medical Center	Roseville	California	United States	95661
27	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
28	Mercy General Hospital Radiation Oncology Center	Sacramento	California	United States	95819
29	California Pacific Medical Center-Pacific Campus	San Francisco	California	United States	94115
30	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California	United States	95065
31	Sutter Pacific Medical Foundation	Santa Rosa	California	United States	95403
32	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California	United States	94086
33	Sutter Cancer Centers Radiation Oncology Services-Vacaville	Vacaville	California	United States	95687
34	Sutter Solano Medical Center/Cancer Center	Vallejo	California	United States	94589
35	Epic Care Cyberknife Center	Walnut Creek	California	United States	94597
36	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
37	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
38	Beebe Medical Center	Lewes	Delaware	United States	19958
39	Christiana Gynecologic Oncology LLC	Newark	Delaware	United States	19713
40	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware	United States	19713
41	Helen F Graham Cancer Center	Newark	Delaware	United States	19713
42	Medical Oncology Hematology Consultants PA	Newark	Delaware	United States	19713
43	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
44	Beebe Health Campus	Rehoboth Beach	Delaware	United States	19971
45	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware	United States	19973
46	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware	United States	19801
47	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida	United States	33442
48	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
49	Miami Cancer Institute	Miami	Florida	United States	33176
50	Piedmont Hospital	Atlanta	Georgia	United States	30309
51	Northside Hospital	Atlanta	Georgia	United States	30342
52	Northside Hospital-Forsyth	Cumming	Georgia	United States	30041
53	Piedmont Fayette Hospital	Fayetteville	Georgia	United States	30214
54	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia	United States	30501
55	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia	United States	31405
56	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
57	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho	United States	83605
58	Idaho Urologic Institute-Meridian	Meridian	Idaho	United States	83642
59	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
60	John H Stroger Jr Hospital of Cook County	Chicago	Illinois	United States	60612
61	UChicago Medicine Comprehensive Cancer Center - Saint Joseph Hospital	Chicago	Illinois	United States	60657
62	Carle on Vermilion	Danville	Illinois	United States	61832
63	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
64	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
65	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
66	Carle Cancer Center	Urbana	Illinois	United States	61801
67	Elkhart Clinic	Elkhart	Indiana	United States	46514-2098
68	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana	United States	46514
69	Elkhart General Hospital	Elkhart	Indiana	United States	46515
70	Radiation Oncology Associates PC	Fort Wayne	Indiana	United States	46804
71	Parkview Hospital Randallia	Fort Wayne	Indiana	United States	46805
72	Parkview Regional Medical Center	Fort Wayne	Indiana	United States	46845
73	Community Howard Regional Health	Kokomo	Indiana	United States	46904
74	IU Health La Porte Hospital	La Porte	Indiana	United States	46350
75	Memorial Regional Cancer Center Day Road	Mishawaka	Indiana	United States	46545
76	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana	United States	46545
77	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana	United States	46545
78	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana	United States	46563
79	Reid Health	Richmond	Indiana	United States	47374
80	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
81	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana	United States	46601
82	South Bend Clinic	South Bend	Indiana	United States	46617
83	Michiana Hematology Oncology PC-Westville	Westville	Indiana	United States	46391
84	Saint Luke's Hospital	Cedar Rapids	Iowa	United States	52402
85	Central Care Cancer Center - Garden City	Garden City	Kansas	United States	67846
86	Central Care Cancer Center - Great Bend	Great Bend	Kansas	United States	67530
87	Kansas Institute of Medicine Cancer and Blood Center	Lenexa	Kansas	United States	66219
88	Minimally Invasive Surgery Hospital	Lenexa	Kansas	United States	66219
89	Menorah Medical Center	Overland Park	Kansas	United States	66209
90	Saint Luke's South Hospital	Overland Park	Kansas	United States	66213
91	Norton Hospital Pavilion and Medical Campus	Louisville	Kentucky	United States	40202
92	Norton Suburban Hospital and Medical Campus	Louisville	Kentucky	United States	40207
93	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
94	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
95	Boston Medical Center	Boston	Massachusetts	United States	02118
96	Bixby Medical Center	Adrian	Michigan	United States	49221
97	Hickman Cancer Center	Adrian	Michigan	United States	49221
98	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
99	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
100	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
101	Spectrum Health Big Rapids Hospital	Big Rapids	Michigan	United States	49307
102	Saint Joseph Mercy Brighton	Brighton	Michigan	United States	48114
103	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan	United States	48183
104	Saint Joseph Mercy Canton	Canton	Michigan	United States	48188
105	Saint Joseph Mercy Chelsea	Chelsea	Michigan	United States	48118
106	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan	United States	48038
107	Beaumont Hospital - Dearborn	Dearborn	Michigan	United States	48124
108	Henry Ford Hospital	Detroit	Michigan	United States	48202
109	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
110	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
111	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
112	Hurley Medical Center	Flint	Michigan	United States	48503
113	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
114	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
115	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
116	Allegiance Health	Jackson	Michigan	United States	49201
117	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
118	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
119	Borgess Medical Center	Kalamazoo	Michigan	United States	49048
120	Sparrow Hospital	Lansing	Michigan	United States	48912
121	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan	United States	48154
122	Mercy Memorial Hospital	Monroe	Michigan	United States	48162
123	Toledo Clinic Cancer Centers-Monroe	Monroe	Michigan	United States	48162
124	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
125	Lakeland Hospital Niles	Niles	Michigan	United States	49120
126	21st Century Oncology-Pontiac	Pontiac	Michigan	United States	48341
127	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
128	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
129	Ascension Saint Mary's Hospital	Saginaw	Michigan	United States	48601
130	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan	United States	49085
131	Marie Yeager Cancer Center	Saint Joseph	Michigan	United States	49085
132	Munson Medical Center	Traverse City	Michigan	United States	49684
133	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
134	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan	United States	48322
135	Metro Health Hospital	Wyoming	Michigan	United States	49519
136	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
137	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
138	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
139	Unity Hospital	Fridley	Minnesota	United States	55432
140	Fairview Clinics and Surgery Center Maple Grove	Maple Grove	Minnesota	United States	55369
141	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
142	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
143	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
144	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
145	Health Partners Inc	Minneapolis	Minnesota	United States	55454
146	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
147	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
148	Regions Hospital	Saint Paul	Minnesota	United States	55101
149	United Hospital	Saint Paul	Minnesota	United States	55102
150	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
151	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
152	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
153	Singing River Hospital	Pascagoula	Mississippi	United States	39581
154	Central Care Cancer Center - Bolivar	Bolivar	Missouri	United States	65613
155	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
156	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri	United States	63141
157	Centerpoint Medical Center LLC	Independence	Missouri	United States	64057
158	Mercy Hospital Joplin	Joplin	Missouri	United States	64804
159	Saint Luke's Hospital of Kansas City	Kansas City	Missouri	United States	64111
160	North Kansas City Hospital	Kansas City	Missouri	United States	64116
161	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri	United States	64118
162	Research Medical Center	Kansas City	Missouri	United States	64132
163	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
164	Liberty Radiation Oncology Center	Liberty	Missouri	United States	64068
165	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri	United States	65401
166	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
167	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
168	Saint Joseph Oncology Inc	Saint Joseph	Missouri	United States	64507
169	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
170	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
171	Siteman Cancer Center-South County	Saint Louis	Missouri	United States	63129
172	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
173	Saint Louis-Cape Girardeau CCOP	Saint Louis	Missouri	United States	63141
174	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri	United States	63376
175	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
176	CoxHealth South Hospital	Springfield	Missouri	United States	65807
177	Renown Regional Medical Center	Reno	Nevada	United States	89502
178	Elliot Hospital	Manchester	New Hampshire	United States	03103
179	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
180	Virtua Memorial	Mount Holly	New Jersey	United States	08060
181	Virtua Voorhees	Voorhees	New Jersey	United States	08043
182	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
183	Memorial Medical Center - Las Cruces	Las Cruces	New Mexico	United States	88011
184	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
185	New York-Presbyterian/Brooklyn Methodist Hospital	Brooklyn	New York	United States	11215
186	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
187	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York	United States	13057
188	Mount Sinai Hospital	New York	New York	United States	10029
189	Highland Hospital	Rochester	New York	United States	14620
190	University of Rochester	Rochester	New York	United States	14642
191	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
192	AdventHealth Hendersonville	Hendersonville	North Carolina	United States	28792
193	Iredell Memorial Hospital	Statesville	North Carolina	United States	28677
194	Summa Health System - Akron Campus	Akron	Ohio	United States	44304
195	Cleveland Clinic Akron General	Akron	Ohio	United States	44307
196	Radiation Oncology Center	Alliance	Ohio	United States	44601
197	Summa Health System - Barberton Campus	Barberton	Ohio	United States	44203
198	Cleveland Clinic Cancer Center Beachwood	Beachwood	Ohio	United States	44122
199	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio	United States	44122
200	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio	United States	43402
201	Cleveland Clinic Mercy Hospital	Canton	Ohio	United States	44708
202	Dayton Physicians LLC-Miami Valley South	Centerville	Ohio	United States	45459
203	Miami Valley Hospital South	Centerville	Ohio	United States	45459
204	Geauga Hospital	Chardon	Ohio	United States	44024
205	Oncology Hematology Care Inc-Kenwood	Cincinnati	Ohio	United States	45236
206	Case Western Reserve University	Cleveland	Ohio	United States	44106
207	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio	United States	44111
208	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
209	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
210	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
211	Miami Valley Hospital	Dayton	Ohio	United States	45409
212	Dayton Physician LLC-Miami Valley Hospital North	Dayton	Ohio	United States	45415
213	Miami Valley Hospital North	Dayton	Ohio	United States	45415
214	Mercy Cancer Center-Elyria	Elyria	Ohio	United States	44035
215	Armes Family Cancer Center	Findlay	Ohio	United States	45840
216	Blanchard Valley Hospital	Findlay	Ohio	United States	45840
217	Orion Cancer Care	Findlay	Ohio	United States	45840
218	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
219	Dayton Physicians LLC-Atrium	Franklin	Ohio	United States	45005
220	Dayton Physicians LLC-Wayne	Greenville	Ohio	United States	45331
221	Wayne Hospital	Greenville	Ohio	United States	45331
222	Cleveland Clinic Cancer Center Independence	Independence	Ohio	United States	44131
223	Kettering Medical Center	Kettering	Ohio	United States	45429
224	Lima Memorial Hospital	Lima	Ohio	United States	45804
225	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio	United States	44906
226	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio	United States	43537
227	Toledo Radiation Oncology at Northwest Ohio Onocolgy Center	Maumee	Ohio	United States	43537
228	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio	United States	44124
229	Summa Health Medina Medical Center	Medina	Ohio	United States	44256
230	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio	United States	44060
231	UH Seidman Cancer Center at Southwest General Hospital	Middleburg Heights	Ohio	United States	44130
232	Saint Charles Hospital	Oregon	Ohio	United States	43616
233	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio	United States	43616
234	University Hospitals Parma Medical Center	Parma	Ohio	United States	44129
235	University Hospitals Portage Medical Center	Ravenna	Ohio	United States	44266
236	UH Seidman Cancer Center at Salem Regional Medical Center	Salem	Ohio	United States	44460
237	North Coast Cancer Care	Sandusky	Ohio	United States	44870
238	Springfield Regional Cancer Center	Springfield	Ohio	United States	45504
239	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
240	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio	United States	44136
241	ProMedica Flower Hospital	Sylvania	Ohio	United States	43560
242	Mercy Hospital of Tiffin	Tiffin	Ohio	United States	44883
243	Saint Vincent Mercy Medical Center	Toledo	Ohio	United States	43608
244	University of Toledo	Toledo	Ohio	United States	43614
245	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio	United States	43617
246	Mercy Health - Saint Anne Hospital	Toledo	Ohio	United States	43623
247	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio	United States	43623
248	Dayton Physicians LLC-Upper Valley	Troy	Ohio	United States	45373
249	Upper Valley Medical Center	Troy	Ohio	United States	45373
250	Fulton County Health Center	Wauseon	Ohio	United States	43567
251	UHHS-Westlake Medical Center	Westlake	Ohio	United States	44145
252	Cancer Treatment Center	Wooster	Ohio	United States	44691
253	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio	United States	44691
254	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
255	Warren Clinic Oncology-Tulsa	Tulsa	Oklahoma	United States	74146
256	Legacy Mount Hood Medical Center	Gresham	Oregon	United States	97030
257	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon	United States	97210
258	Jefferson Abington Hospital	Abington	Pennsylvania	United States	19001
259	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	United States	18103
260	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
261	Pocono Medical Center	East Stroudsburg	Pennsylvania	United States	18301
262	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
263	Reading Hospital	West Reading	Pennsylvania	United States	19611
264	AnMed Health Cancer Center	Anderson	South Carolina	United States	29621
265	Medical University of South Carolina	Charleston	South Carolina	United States	29425
266	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina	United States	29341
267	Gibbs Cancer Center-Pelham	Greer	South Carolina	United States	29651
268	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
269	Covenant Medical Center-Lakeside	Lubbock	Texas	United States	79410
270	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
271	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont	United States	05602
272	University of Vermont Medical Center	Burlington	Vermont	United States	05401
273	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
274	Fredericksburg Oncology Inc	Fredericksburg	Virginia	United States	22401
275	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
276	Legacy Salmon Creek Hospital	Vancouver	Washington	United States	98686
277	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia	United States	26003
278	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
279	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
280	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
281	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
282	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin	United States	53038
283	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
284	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
285	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
286	Ascension Columbia Saint Mary's Hospital Ozaukee	Mequon	Wisconsin	United States	53097
287	Ascension Columbia Saint Mary's Hospital - Milwaukee	Milwaukee	Wisconsin	United States	53211
288	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
289	Cancer Center of Western Wisconsin	New Richmond	Wisconsin	United States	54017
290	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin	United States	54154
291	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235-1495
292	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
293	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8V 5C2
294	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
295	Keimyung University-Dongsan Medical Center	Dalseo-gu	Daegu	Korea, Republic of	42601
296	National Cancer Center-Korea	Goyang-si	Gyeonggi-do	Korea, Republic of	410-769
297	Chonnam National University Hwasun Hospital	Hwasun-gun	Jeollanam-do	Korea, Republic of	519-763
298	Samsung Medical Center	Seoul	Korea	Korea, Republic of	135-710
299	Seoul National University Bundang Hospital	Seongnam City	Kyeonggi-do	Korea, Republic of	463-707
300	Gangnam Severance Hospital	Seoul		Korea, Republic of	06273
301	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
302	Yonsei University Health System-Severance Hospital	Seoul		Korea, Republic of	120-752

Sponsors and Collaborators

• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: In A Kim, NRG Oncology

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 2, 2019

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01622868
• Other Study ID Numbers: NCI-2012-01977; NCI-2012-01977; RTOG-1119; CDR0000735353; RTOG-1119; RTOG-1119; U10CA180868; U10CA021661
• First Posted: Jun 19, 2012
• Last Update Posted: Jul 21, 2022
• Last Verified: May 1, 2022

• Additional relevant MeSH terms: Carcinoma; Breast Neoplasms; Brain Neoplasms; Neoplasms; Lapatinib

Study Results

Participant Flow

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Period Title: Overall Study
STARTED	72	71
Eligible	65	71
Eligible, Started Study Treatment, Has Adverse Event Data	63	71
COMPLETED	65	71
NOT COMPLETED	7	0

Baseline Characteristics

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy	Total
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))	Total of all reporting groups
Overall Participants	65	71	136
Age, Customized (Count of Participants)
< 50 years	22 33.8%	25 35.2%	47 34.6%
≥ 50 years	43 66.2%	46 64.8%	89 65.4%
Sex: Female, Male (Count of Participants)
Female	65 100%	71 100%	136 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 12.3%	3 4.2%	11 8.1%
Not Hispanic or Latino	57 87.7%	67 94.4%	124 91.2%
Unknown or Not Reported	0 0%	1 1.4%	1 0.7%
Karnofsky Performance Status (Count of Participants)
60	9 13.8%	2 2.8%	11 8.1%
70-80	29 44.6%	27 38%	56 41.2%
90-100	27 41.5%	42 59.2%	69 50.7%
Graded Prognostic Assessment for Breast Cancer (Breast-GPA) (Count of Participants)
1.5-2.0	5 7.7%	4 5.6%	9 6.6%
2.5-3.0	35 53.8%	37 52.1%	72 52.9%
3.5-4.0	25 38.5%	30 42.3%	55 40.4%
Use of Non-central nervous system (CNS) penetrating HER2 Blockade at Study Entry (Count of Participants)
No (None)	23 35.4%	28 39.4%	51 37.5%
Yes (Trastuzumab and/or Pertuzumab)	42 64.6%	43 60.6%	85 62.5%
Previous Stereotactic SRS or Surgery (Count of Participants)
No	37 56.9%	41 57.7%	78 57.4%
Yes	5 7.7%	6 8.5%	11 8.1%
Planned RT (Count of Participants)
SRS	6 9.2%	6 8.5%	12 8.8%
WBRT	59 90.8%	65 91.5%	124 91.2%

Outcome Measures

1. Primary Outcome

Title	Complete Response (CR) Rate in the Brain at 12 Weeks Post-radiation Therapy (RT) Using the RECIST 1.1 Criteria Based on Brain Magnetic Resonance Imaging (MRI)
Description	The Response Evaluation Criteria in Solid Tumors (RECIST) criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.
Time Frame	Baseline and 12 weeks post RT (approximately 12 weeks from start of treatment if SRS and 15 if WBRT)

Outcome Measure Data

Analysis Population Description

Evaluable data for determining the 12-week post-RT RECIST response was available for 52 eligible participants on the RT alone arm and 64 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	52	64
Number [percentage of participants]	5.8 8.9%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy, Lapatinib and Radiation Therapy
	Comments	The study was designed to see if there is a signal in the 12-week CR rate with the addition of lapatinib to warrant a future phase III trial. Null hypothesis: the 12-week post-WBRT/SRS CR rate is ≤ 5%; alternative hypothesis: the addition of lapatinib will increase that CR rate to at least 20%. 114 eligible participants provide 86% power to detect a 15% absolute increase in CR rate at a significance level of 0.10, using a 1-sided Z-test for the difference of 2 proportions.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments	One-sided significance level = 0.10
	Method	Z-test
	Comments

2. Secondary Outcome

Title	Complete Response Rate in the Brain at 4 Weeks Post-RT Using the RECIST 1.1 Criteria Based on Brain MRI
Description	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.
Time Frame	Baseline and 4 weeks post RT (approximately 4 weeks from start of treatment if SRS and 7 if WBRT)

Outcome Measure Data

Analysis Population Description

Evaluable data for determining the 4-week post-RT RECIST response was available for 55 eligible participants on the RT alone arm and 67 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	55	67
Number [percentage of participants]	3.6 5.5%	1.5 2.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy, Lapatinib and Radiation Therapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments	One-sided significance level = 0.10
	Method	Z-test
	Comments

3. Secondary Outcome

Title	Complete Response Rate in the Brain Using the World Health Organization (WHO)/Modified McDonald Criteria Based on Brain MRI
Description	The WHO/modified McDonald Criteria evaluates changes in bidimensional tumor measurements. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.
Time Frame	Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)

Outcome Measure Data

Analysis Population Description

Evaluable data for determining the 4- and 12-week post-RT WHO response was available for 55 eligible participants at week 4 and 52 at week 12 on the RT alone arm and 67 at week 4 and 64 at week 12 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	65	71
4 weeks post-RT	3.6 5.5%	1.5 2.1%
12 weeks post-RT	5.8 8.9%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy, Lapatinib and Radiation Therapy
	Comments	4 weeks post-RT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments	One-sided significance level = 0.10
	Method	Z-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy, Lapatinib and Radiation Therapy
	Comments	12 weeks post-RT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments	One-sided significance level = 0.10
	Method	Z-test
	Comments

4. Secondary Outcome

Title	Objective Response Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI
Description	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Objective response is defined as a complete or partial response. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Partial response is defined as ≥ 30% reduction in the sum of diameters of up to 2 of the largest target lesions. Rate is calculated by dividing the number of patients with objective response by the number of analyzable patients.
Time Frame	Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)

Outcome Measure Data

Analysis Population Description

Evaluable data for determining the 4- and 12-week post-RT RECIST response was available for 55 eligible participants at week 4 and 52 at week 12 on the RT alone arm and 67 at week 4 and 64 at week 12 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	65	71
4 weeks post-RT	41.8 64.3%	55.2 77.7%
12 weeks post-RT	59.6 91.7%	46.9 66.1%

5. Secondary Outcome

Title	Percentage of Participants With Progression in the Brain Outside the Targeted Measurable Disease Using the RECIST 1.1 Criteria Based on Brain MRI
Description	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. CNS progressive disease outside the targeted measureable disease was determined by a retrospective central review of MRI scans by the study neuroradiology co-chair and is defined as the first occurrence since baseline of new lesions or progression of non-target lesions. Time to CNS progressive disease is defined as time from randomization to the date of progressive disease, last known follow-up (censored), or death (competing risk). Progression rates are estimated using the cumulative incidence method. One-year rates are provided.
Time Frame	From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.

Outcome Measure Data

Analysis Population Description

MRI scans were available for central review for progression outside targeted measurable disease for 41 eligible participants on the RT alone arm and 57 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	41	57
Number (95% Confidence Interval) [percentage of participants]	22.0 33.8%	37.7 53.1%

6. Secondary Outcome

Title	Targeted Lesion-specific Objective Response Rate Using the RECIST 1.1 Measurement Criteria Based on Brain MRI
Description	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Objective response is defined as a complete or partial response. Complete response is defined as the complete disappearance of all enhancing disease and partial response is defined as ≥ 30% reduction in the diameter of the target lesion. Lesions were evaluated individually. Rate is calculated by dividing the number of lesions with objective response by the number of analyzable lesions.
Time Frame	Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)

Outcome Measure Data

Analysis Population Description

Evaluable data for determining the 4- and 12-week post-RT RECIST target lesion measurement response was available for 51 eligible participants at week 4 and 43 at week 12 on the RT alone arm and 66 at week 4 and 57 at week 12 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	65	71
Measure lesions	90	116
4 weeks post-RT	51.1	56.0
12 weeks post-RT	75.0	61.4

7. Secondary Outcome

Title	Targeted Lesion-specific Progression Rate Using the RECIST 1.1 Measurement Criteria Based on Brain MRI
Description	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Progression is defined as ≥ 20% increase in the diameter of the target lesion relative to nadir. Lesions were evaluated individually. Rate is calculated by dividing the number of lesions with progression by the number of analyzable lesions.
Time Frame	Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)

Outcome Measure Data

Analysis Population Description

Evaluable data for determining the 4- and 12-week post-RT RECIST target lesion measurement response was available for 51 eligible participants at week 4 and 43 at week 12 on the RT alone arm and 66 at week 4 and 57 at week 12 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	65	71
Measure lesions	90	116
4 weeks post-RT	3.3	1.7
12 weeks post-RT	6.6	14.9

8. Secondary Outcome

Title	Frequency of Highest Treatment-related Adverse Event Per Participant
Description	Adverse events reported as definitely, probably, or possibly related to protocol treatment. Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data provided in this outcome measure. See Adverse Events Module for specific Adverse Event data.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 71.6 months.

Outcome Measure Data

Analysis Population Description

Eligible participants who started study treatment and have adverse event data.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	63	71
Grade 1	8 12.3%	14 19.7%
Grade 2	23 35.4%	20 28.2%
Grade 3	5 7.7%	20 28.2%
Grade 4	0 0%	4 5.6%
Grade 5	0 0%	0 0%

9. Secondary Outcome

Title	Overall Complete Response Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI
Description	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Overall complete response is defined as the complete disappearance of all CNS target lesions sustained for at least 4 weeks; with no new lesions, no use of corticosteroids, and patient is stable or improved clinically. All site-reported MRI data and all site-reporting of clinical progressive disease indicators were used in this analysis. Rate is calculated by dividing the number of participants with overall complete response by the number of analyzable participants.
Time Frame	From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.

Outcome Measure Data

Analysis Population Description

Evaluable data for determining overall post-RT RECIST response was available for 54 eligible participants on the RT alone arm and 68 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	54	68
Count of Participants [Participants]	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy, Lapatinib and Radiation Therapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	One-sided significance level = 0.10
	Method	z-test
	Comments

10. Secondary Outcome

Title	Overall Progression Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI
Description	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Overall progression is defined as unequivocal progression, new or worsening tumor-related neurological symptoms, tumor-related increase in steroid dose, new primary in brain, or progression in target lesions. All site-reported MRI data and all site-reporting of clinical progressive disease indicators were used in this analysis. Rate is calculated by dividing the number of participants with progression by the number of analyzable participants.
Time Frame	From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.

Outcome Measure Data

Analysis Population Description

Evaluable data for determining overall post-RT RECIST response was available for 54 eligible participants on the RT alone arm and 68 on the lapatinib arm.

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	54	68
Count of Participants [Participants]	38 58.5%	54 76.1%

11. Secondary Outcome

Title	Overall Survival (OS)
Description	An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. Analysis occurred after 101 deaths were reported.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 71.6 months.

Outcome Measure Data

Analysis Population Description

Eligible participants

Arm/Group Title	Radiation Therapy	Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)	1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
Measure Participants	65	71
Median (95% Confidence Interval) [months]	15.6	15.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiation Therapy, Lapatinib and Radiation Therapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments	Two-sided significance level = 0.05
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Weekly during radiation therapy and lapatinib (when applicable), 4 weeks post-RT completion, 12 weeks post-RT completion, every 3 months to year 3, and then annually. Maximum follow-up at time of analysis was 71.6 months.
Arm/Group Title	Radiation Therapy		Lapatinib and Radiation Therapy
Arm/Group Description	Stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT)		1000 mg Lapatinib for six weeks with radiation therapy (stereotactic radiosurgery (SRS) or 3 weeks of whole brain radiotherapy (WBRT))
All Cause Mortality
	Radiation Therapy		Lapatinib and Radiation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/63 (76.2%)		53/71 (74.6%)
Serious Adverse Events
	Radiation Therapy		Lapatinib and Radiation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/63 (27%)		16/71 (22.5%)
Blood and lymphatic system disorders
Anemia	1/63 (1.6%)		2/71 (2.8%)
Febrile neutropenia	1/63 (1.6%)		0/71 (0%)
Cardiac disorders
Cardiac arrest	1/63 (1.6%)		0/71 (0%)
Ear and labyrinth disorders
Ear pain	1/63 (1.6%)		0/71 (0%)
Eye disorders
Eye disorders - Other, specify	0/63 (0%)		1/71 (1.4%)
Gastrointestinal disorders
Colonic obstruction	1/63 (1.6%)		0/71 (0%)
Diarrhea	0/63 (0%)		1/71 (1.4%)
Nausea	1/63 (1.6%)		1/71 (1.4%)
Vomiting	1/63 (1.6%)		1/71 (1.4%)
General disorders
Fatigue	1/63 (1.6%)		1/71 (1.4%)
Fever	1/63 (1.6%)		1/71 (1.4%)
Gait disturbance	2/63 (3.2%)		0/71 (0%)
General disorders and administration site conditions - Other, specify	1/63 (1.6%)		0/71 (0%)
Infections and infestations
Endocarditis infective	1/63 (1.6%)		0/71 (0%)
Lung infection	1/63 (1.6%)		1/71 (1.4%)
Sepsis	0/63 (0%)		1/71 (1.4%)
Investigations
Alanine aminotransferase increased	1/63 (1.6%)		2/71 (2.8%)
Alkaline phosphatase increased	1/63 (1.6%)		0/71 (0%)
Blood bilirubin increased	0/63 (0%)		1/71 (1.4%)
Neutrophil count decreased	0/63 (0%)		1/71 (1.4%)
Platelet count decreased	0/63 (0%)		3/71 (4.2%)
White blood cell decreased	0/63 (0%)		1/71 (1.4%)
Metabolism and nutrition disorders
Anorexia	1/63 (1.6%)		0/71 (0%)
Dehydration	1/63 (1.6%)		1/71 (1.4%)
Hyperkalemia	1/63 (1.6%)		1/71 (1.4%)
Hypoalbuminemia	1/63 (1.6%)		0/71 (0%)
Hypokalemia	0/63 (0%)		1/71 (1.4%)
Hyponatremia	0/63 (0%)		1/71 (1.4%)
Musculoskeletal and connective tissue disorders
Back pain	1/63 (1.6%)		0/71 (0%)
Muscle weakness left-sided	1/63 (1.6%)		0/71 (0%)
Muscle weakness lower limb	1/63 (1.6%)		0/71 (0%)
Nervous system disorders
Dizziness	1/63 (1.6%)		0/71 (0%)
Encephalopathy	0/63 (0%)		1/71 (1.4%)
Headache	3/63 (4.8%)		0/71 (0%)
Intracranial hemorrhage	1/63 (1.6%)		0/71 (0%)
Leukoencephalopathy	0/63 (0%)		1/71 (1.4%)
Memory impairment	0/63 (0%)		1/71 (1.4%)
Seizure	1/63 (1.6%)		1/71 (1.4%)
Somnolence	1/63 (1.6%)		0/71 (0%)
Psychiatric disorders
Confusion	0/63 (0%)		1/71 (1.4%)
Renal and urinary disorders
Acute kidney injury	0/63 (0%)		1/71 (1.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/63 (1.6%)		1/71 (1.4%)
Hypoxia	1/63 (1.6%)		0/71 (0%)
Pleural effusion	1/63 (1.6%)		0/71 (0%)
Respiratory failure	1/63 (1.6%)		0/71 (0%)
Skin and subcutaneous tissue disorders
Alopecia	1/63 (1.6%)		0/71 (0%)
Nail loss	1/63 (1.6%)		0/71 (0%)
Rash acneiform	0/63 (0%)		1/71 (1.4%)
Rash maculo-papular	0/63 (0%)		1/71 (1.4%)
Vascular disorders
Hypotension	1/63 (1.6%)		0/71 (0%)
Thromboembolic event	1/63 (1.6%)		2/71 (2.8%)
Vascular disorders - Other, specify	1/63 (1.6%)		0/71 (0%)
Other (Not Including Serious) Adverse Events
	Radiation Therapy		Lapatinib and Radiation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/63 (77.8%)		63/71 (88.7%)
Blood and lymphatic system disorders
Anemia	5/63 (7.9%)		18/71 (25.4%)
Eye disorders
Blurred vision	7/63 (11.1%)		9/71 (12.7%)
Eye disorders - Other, specify	2/63 (3.2%)		4/71 (5.6%)
Gastrointestinal disorders
Abdominal pain	4/63 (6.3%)		0/71 (0%)
Constipation	5/63 (7.9%)		11/71 (15.5%)
Diarrhea	5/63 (7.9%)		31/71 (43.7%)
Dry mouth	3/63 (4.8%)		6/71 (8.5%)
Dyspepsia	3/63 (4.8%)		8/71 (11.3%)
Mucositis oral	1/63 (1.6%)		9/71 (12.7%)
Nausea	16/63 (25.4%)		38/71 (53.5%)
Vomiting	11/63 (17.5%)		21/71 (29.6%)
General disorders
Edema limbs	4/63 (6.3%)		9/71 (12.7%)
Fatigue	27/63 (42.9%)		40/71 (56.3%)
Gait disturbance	4/63 (6.3%)		11/71 (15.5%)
Pain	10/63 (15.9%)		7/71 (9.9%)
Infections and infestations
Urinary tract infection	1/63 (1.6%)		4/71 (5.6%)
Injury, poisoning and procedural complications
Dermatitis radiation	1/63 (1.6%)		5/71 (7%)
Fall	1/63 (1.6%)		7/71 (9.9%)
Investigations
Alanine aminotransferase increased	2/63 (3.2%)		12/71 (16.9%)
Alkaline phosphatase increased	1/63 (1.6%)		8/71 (11.3%)
Aspartate aminotransferase increased	1/63 (1.6%)		10/71 (14.1%)
Blood bilirubin increased	1/63 (1.6%)		9/71 (12.7%)
Lymphocyte count decreased	3/63 (4.8%)		17/71 (23.9%)
Platelet count decreased	3/63 (4.8%)		12/71 (16.9%)
Weight loss	3/63 (4.8%)		7/71 (9.9%)
White blood cell decreased	1/63 (1.6%)		11/71 (15.5%)
Metabolism and nutrition disorders
Anorexia	12/63 (19%)		19/71 (26.8%)
Dehydration	0/63 (0%)		5/71 (7%)
Hyperglycemia	4/63 (6.3%)		10/71 (14.1%)
Hypoalbuminemia	1/63 (1.6%)		11/71 (15.5%)
Hypocalcemia	2/63 (3.2%)		7/71 (9.9%)
Hypokalemia	0/63 (0%)		9/71 (12.7%)
Hypomagnesemia	0/63 (0%)		4/71 (5.6%)
Hyponatremia	2/63 (3.2%)		9/71 (12.7%)
Musculoskeletal and connective tissue disorders
Back pain	6/63 (9.5%)		8/71 (11.3%)
Generalized muscle weakness	7/63 (11.1%)		12/71 (16.9%)
Muscle weakness lower limb	6/63 (9.5%)		6/71 (8.5%)
Musculoskeletal and connective tissue disorder - Other, specify	2/63 (3.2%)		4/71 (5.6%)
Myalgia	1/63 (1.6%)		5/71 (7%)
Pain in extremity	3/63 (4.8%)		4/71 (5.6%)
Nervous system disorders
Ataxia	3/63 (4.8%)		4/71 (5.6%)
Cognitive disturbance	4/63 (6.3%)		2/71 (2.8%)
Dizziness	7/63 (11.1%)		19/71 (26.8%)
Dysarthria	1/63 (1.6%)		4/71 (5.6%)
Dysgeusia	3/63 (4.8%)		9/71 (12.7%)
Headache	21/63 (33.3%)		27/71 (38%)
Lethargy	0/63 (0%)		4/71 (5.6%)
Memory impairment	11/63 (17.5%)		9/71 (12.7%)
Nervous system disorders - Other, specify	4/63 (6.3%)		2/71 (2.8%)
Paresthesia	5/63 (7.9%)		6/71 (8.5%)
Peripheral sensory neuropathy	7/63 (11.1%)		10/71 (14.1%)
Seizure	2/63 (3.2%)		5/71 (7%)
Psychiatric disorders
Anxiety	2/63 (3.2%)		8/71 (11.3%)
Confusion	2/63 (3.2%)		6/71 (8.5%)
Depression	3/63 (4.8%)		10/71 (14.1%)
Insomnia	3/63 (4.8%)		13/71 (18.3%)
Respiratory, thoracic and mediastinal disorders
Cough	4/63 (6.3%)		7/71 (9.9%)
Dyspnea	7/63 (11.1%)		13/71 (18.3%)
Skin and subcutaneous tissue disorders
Alopecia	19/63 (30.2%)		24/71 (33.8%)
Dry skin	2/63 (3.2%)		7/71 (9.9%)
Erythema multiforme	2/63 (3.2%)		5/71 (7%)
Palmar-plantar erythrodysesthesia syndrome	1/63 (1.6%)		5/71 (7%)
Pruritus	2/63 (3.2%)		5/71 (7%)
Rash acneiform	1/63 (1.6%)		18/71 (25.4%)
Rash maculo-papular	1/63 (1.6%)		10/71 (14.1%)
Skin and subcutaneous tissue disorders - Other, specify	3/63 (4.8%)		7/71 (9.9%)
Skin hyperpigmentation	3/63 (4.8%)		4/71 (5.6%)
Vascular disorders
Hypertension	2/63 (3.2%)		11/71 (15.5%)
Lymphedema	3/63 (4.8%)		5/71 (7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Must obtain prior approval from the sponsor. In addition, PI's are required to abide by the collaborator's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.