Radiation Therapy and Stereotactic Radiosurgery With or Without Temozolomide or Erlotinib in Treating Patients With Brain Metastases Secondary to Non-Small Cell Lung Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00096265
• Collaborator: Radiation Therapy Oncology Group (Other)
• Enrollment: 126
• Locations: 83
• Arms: 3
• Actual Duration (Months): 89.8
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase III trial is studying whole-brain radiation therapy and stereotactic radiosurgery with or without temozolomide or erlotinib to see how well they work compared to whole-brain radiation therapy and stereotactic radiosurgery in treating patients with brain metastases secondary to non-small cell lung cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth and by blocking blood flow to the tumor. It is not yet known whether radiation therapy and stereotactic radiosurgery are more effective with or without temozolomide or erlotinib in treating brain metastases.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Malignant Neoplasm in the Brain; Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer AJCC v7	Radiation: 3-Dimensional Conformal Radiation Therapy; Drug: Erlotinib Hydrochloride; Radiation: Stereotactic Radiosurgery; Drug: Temozolomide	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. Compare survival in patients with non-small cell lung cancer and brain metastases treated with whole brain radiotherapy and stereotactic radiosurgery with vs without temozolomide or erlotinib.

SECONDARY OBJECTIVES:

1. Compare time to CNS progression in patients treated with these regimens. II. Compare quality-adjusted survival in patients treated with these regimens. III. Compare 3-month quality of life in patients treated with these regimens. IV. Compare the 6-month performance status of patients treated with these regimens.

2. Compare 6-month steroid dependence in patients treated with these regimens. VI. Compare cause of death (neurologic vs other) in patients treated with these regimens.

3. Determine the effects of non-protocol chemotherapy in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age and the presence of extracranial metastases (< 65 years old AND no extracranial metastases vs ≥ 65 years old OR extracranial metastases), number of metastases (1 vs 2 or 3), and extent of extracranial disease (none vs present). Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.

ARM II: Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM III: Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.

In all arms, patients with recurrent brain metastases may undergo additional stereotactic radiosurgery.

Quality of life is assessed at baseline and at 3, 6, 9, 12, 18, and 24 months.

Patients are followed every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Trial Comparing Whole Brain Radiation and Stereotactic Radiosurgery Alone Versus With Temozolomide or Erlotinib in Patients With Non-Small Cell Lung Cancer and 1-3 Brain Metastases
• Actual Study Start Date: Oct 6, 2004
• Actual Primary Completion Date: Jun 14, 2011
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Radiation: 3-Dimensional Conformal Radiation Therapy; Patients undergo radiation therapy once daily for approximately 3 weeks; Other Names: 3-dimensional radiation therapy 3D CONFORMAL RADIATION THERAPY 3D CRT 3D-CRT Conformal Therapy Radiation Conformal Therapy ; Radiation: Stereotactic Radiosurgery; Patients undergo surgery after radiation therapy; Other Names: Stereotactic External Beam Irradiation stereotactic external-beam radiation therapy stereotactic radiation therapy Stereotactic Radiotherapy stereotaxic radiation therapy stereotaxic radiosurgery
Experimental: Arm II Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Radiation: 3-Dimensional Conformal Radiation Therapy; Patients undergo radiation therapy once daily for approximately 3 weeks; Other Names: 3-dimensional radiation therapy 3D CONFORMAL RADIATION THERAPY 3D CRT 3D-CRT Conformal Therapy Radiation Conformal Therapy ; Radiation: Stereotactic Radiosurgery; Patients undergo surgery after radiation therapy; Other Names: Stereotactic External Beam Irradiation stereotactic external-beam radiation therapy stereotactic radiation therapy Stereotactic Radiotherapy stereotaxic radiation therapy stereotaxic radiosurgery ; Drug: Temozolomide; Given orally; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm III Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.	Radiation: 3-Dimensional Conformal Radiation Therapy; Patients undergo radiation therapy once daily for approximately 3 weeks; Other Names: 3-dimensional radiation therapy 3D CONFORMAL RADIATION THERAPY 3D CRT 3D-CRT Conformal Therapy Radiation Conformal Therapy ; Drug: Erlotinib Hydrochloride; Given orally; Other Names: Cp-358,774 OSI-774 Tarceva ; Radiation: Stereotactic Radiosurgery; Patients undergo surgery after radiation therapy; Other Names: Stereotactic External Beam Irradiation stereotactic external-beam radiation therapy stereotactic radiation therapy Stereotactic Radiotherapy stereotaxic radiation therapy stereotaxic radiosurgery

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From randomization to date of death or last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.]

   Survival time is defined as time from randomization to date of death from any cause and estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact.

Secondary Outcome Measures

1. Rate of CNS Progression (One Year) [From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.]

   CNS progression is defined as any increase in perpendicular bi-dimensional tumor area for any of the 1-3 tracked brain metastases, by any amount, or the appearance of any new brain metastasis on a follow-up MRI (SRS planning scan will not be used to evaluate CNS progression). For lesions smaller than 1 cm in maximum diameter, a maximum increase of 50% in perpendicular bi-dimensional treatment area is necessary to score as progression. This caveat is included to account for potential variability in measurement, which is most susceptible to proportionate errors at smaller sizes. For greater than 1 cm lesions, the definition uses a 25% rule for change. Rates of CNS progression estimated by the cumulative incidence method, with death treated as a competing risk.

2. Quality-adjusted Survival as Measured by EuroQol 5-dimension Instrument [From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.]

   Quality-adjusted life years (QALY) incorporate the societal-based utilities of health states into expected life years for a health condition. The QALY model is QALY(h,y) where h is a health state and y is the years of life. Higher quality-adjusted life year values represent a better outcome. A patient's health state will be determined from the index score of the EQ-5D-5L patient questionnaire.The EQ-5D-5L is a 2-part self-assessment questionnaire, a 5-item index score and a visual analogue scale, but only the index score is used for quality-adjusted survival. The index score has 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state).

3. Change in Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 Months [From randomization to three months.]

   The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score, which ranges from 0 to 76. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-Br including the FACT-G must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicates better QOL. A change of 5 points will be considered a minimal clinically meaningful change. Change from baseline at three months (3 month score - baseline score) will be categorized as improvement if increased, stable if no change, or deterioration if decreased.

4. Change in Performance Status at Six Months [From randomization to six months.]

   Compared between two treatment arms using a two-group chi-squared test. Zubrod score will be collected at baseline and follow-up. The Zubrod performance score runs from 0 to 5, with 0 denoting perfect health and 5 death. Change from baseline is calculated as 6-month value - baseline value. Patients with a baseline score who have died by six months will be included in the analysis with a score of 5 at six months.

5. Change in Steroid Dependence at Six Months [From randomization to six months.]

   Daily steroid dose will be collected at baseline and follow-up, as one of the following: 0-4 mg, >4 to ≤ 8 mg, >8 to ≤12 mg, and >12 mg. Change from baseline at six months will be evaluated to have decreased, remained stable, or increased, based on these categories.

6. Cause of Death (Neurologic vs Other) [From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.]

   Patients were considered to have died neurologic deaths (coded as "Brain Metastases") if they had stable systemic disease and progressive neurologic disease consisting of expanding intracranial masses, CNS hemorrhages, hydrocephalus resulting in herniation or fulminant meningeal carcinomatosis.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed non-small cell lung cancer

• One to 3 intraparenchymal brain metastases by contrast-enhanced MRI, meeting the following criteria:

• Well circumscribed tumor(s)

• Maximum diameter ≤ 4.0 cm

• If multiple lesions are present and one lesion is at the maximum diameter, the other lesions must not exceed 3.0 cm in maximum diameter

• No metastases within 10 mm of the optic apparatus such that a portion of the optic nerve or chiasm would be included in the high-dose stereotactic radiosurgery boost field

• No metastases in the brainstem, midbrain, pons, or medulla

• No prior complete resection of all known brain metastases

• Subtotal resection allowed provided residual disease is ≤ 4.0 cm in maximum diameter

• No clinical or radiographic evidence of progression (other than study lesion[s]) within the past month

• Patients with brain metastases at initial presentation do not require 1 month of scans documenting stable disease

• Stable extracranial metastases allowed

• No known or pre-existing liver metastases

• No leptomeningeal metastases by MRI or cerebrospinal fluid evaluation

• Synchronous brain metastases at initial diagnosis allowed

• Performance status - Zubrod 0-1

• Hemoglobin ≥ 8 g/dL

• Absolute neutrophil count ≥ 1,000/mm^3

• Platelet count ≥ 100,000/mm^3

• AST < 2 times upper limit of normal (ULN)

• Alkaline phosphatase < 2 times ULN unless due to elevated bone metastases

• Total bilirubin normal

• Lactic dehydrogenase < 2 times ULN

• Creatinine < 1.5 times ULN

• No clinically active interstitial lung disease

• Chronic stable asymptomatic radiographic changes allowed

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• HIV negative

• Neurologic function status 0-2

• No other major medical illness or psychiatric impairment that would preclude study participation

• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to erlotinib or temozolomide

• No concurrent immunotherapy

• No concurrent biologic therapy, excluding growth factors and epoetin alfa

• No prior temozolomide or erlotinib

• No other concurrent chemotherapy during study radiotherapy

• Other concurrent chemotherapy allowed after study radiotherapy, except for the following:

• Temozolomide or erlotinib (arm I only)

• Erlotinib (arm II only)

• Temozolomide (arm III only)

• No prior cranial radiotherapy

• No concurrent intensity-modulated radiotherapy

• Concurrent radiotherapy to painful bone lesions allowed

• No concurrent radiotherapy to more than 15% of bone marrow

• No other concurrent therapy for brain metastases unless a recurrence is detected

• More than 30 days since prior investigational drugs

• No concurrent enzyme-inducing antiepileptic drugs including, but not limited to, any of the following (for patients randomized to receive erlotinib):

• Phenytoin

• Carbamazepine

• Rifampin

• Phenobarbital

• Primidone

• Oxcarbazepine

• No other concurrent investigational drugs

• No concurrent Hypericum perforatum (St. John's wort)

• No drugs that alter gastric pH (e.g., proton pump inhibitors or H2 antagonists) within 4 hours after erlotinib administration (arm III patients only)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Oncology Services Foundation	Scottsdale	Arizona	United States	85260
2	Scottsdale Health Care-Osborn	Scottsdale	Arizona	United States	85260
3	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California	United States	91505
4	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California	United States	90027
5	Pomona Valley Hospital Medical Center	Pomona	California	United States	91767
6	Saint Mary's Hospital and Regional Medical Center	Grand Junction	Colorado	United States	81501
7	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
8	Integrated Community Oncology Network-Florida Cancer Center Beaches	Jacksonville Beach	Florida	United States	32250
9	Baptist MD Anderson Cancer Center	Jacksonville	Florida	United States	32207
10	Integrated Community Oncology Network-Southside Cancer Center	Jacksonville	Florida	United States	32207
11	Baptist Medical Center South	Jacksonville	Florida	United States	32258
12	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
13	21st Century Oncology-Orange Park	Orange Park	Florida	United States	32073
14	UF Cancer Center at Orlando Health	Orlando	Florida	United States	32806
15	21st Century Oncology-Palatka	Palatka	Florida	United States	32177
16	Bay Medical Center	Panama City	Florida	United States	32401
17	Integrated Community Oncology Network-Flager Cancer Center	Saint Augustine	Florida	United States	32086
18	Tallahassee Memorial HealthCare	Tallahassee	Florida	United States	32308
19	John B Amos Cancer Center	Columbus	Georgia	United States	31904
20	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
21	Northwest Community Hospital	Arlington Heights	Illinois	United States	60005
22	Northwestern University	Chicago	Illinois	United States	60611
23	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
24	Saint John's Hospital	Springfield	Illinois	United States	62702
25	Parkview Hospital Randallia	Fort Wayne	Indiana	United States	46805
26	Franciscan Saint Margaret Health-Hammond Campus	Hammond	Indiana	United States	46320
27	IU Health Methodist Hospital	Indianapolis	Indiana	United States	46202
28	Finley Hospital	Dubuque	Iowa	United States	52001
29	Norton Suburban Hospital and Medical Campus	Louisville	Kentucky	United States	40207
30	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
31	Saint Agnes Hospital	Baltimore	Maryland	United States	21229
32	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
33	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
34	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
35	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
36	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
37	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
38	Fairview-Southdale Hospital	Edina	Minnesota	United States	55435
39	Unity Hospital	Fridley	Minnesota	United States	55432
40	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
41	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
42	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
43	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota	United States	56303
44	Saint Cloud Hospital	Saint Cloud	Minnesota	United States	56303
45	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
46	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
47	United Hospital	Saint Paul	Minnesota	United States	55102
48	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
49	Saint Louis University Hospital	Saint Louis	Missouri	United States	63110
50	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
51	Renown Regional Medical Center	Reno	Nevada	United States	89502
52	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
53	Riverview Medical Center/Booker Cancer Center	Red Bank	New Jersey	United States	07701
54	Sparta Cancer Treatment Center	Sparta	New Jersey	United States	07871
55	University of Rochester	Rochester	New York	United States	14642
56	Mission Hospital-Memorial Campus	Asheville	North Carolina	United States	28801
57	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio	United States	44304
58	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
59	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
60	Delaware County Memorial Hospital	Drexel Hill	Pennsylvania	United States	19026
61	Radiation Therapy Oncology Group	Philadelphia	Pennsylvania	United States	19103
62	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
63	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
64	Reading Hospital	West Reading	Pennsylvania	United States	19611
65	Medical University of South Carolina	Charleston	South Carolina	United States	29425
66	Thompson Cancer Survival Center	Knoxville	Tennessee	United States	37916
67	Arlington Cancer Center	Arlington	Texas	United States	76012
68	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
69	University of Texas Medical Branch	Galveston	Texas	United States	77555-0565
70	M D Anderson Cancer Center	Houston	Texas	United States	77030
71	Intermountain Medical Center	Murray	Utah	United States	84107
72	McKay-Dee Hospital Center	Ogden	Utah	United States	84403
73	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
74	LDS Hospital	Salt Lake City	Utah	United States	84143
75	Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
76	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
77	Virginia Mason Medical Center	Seattle	Washington	United States	98101
78	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
79	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
80	Wheaton Franciscan Cancer Care - All Saints	Racine	Wisconsin	United States	53405
81	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
82	Ottawa Hospital-Civic Campus	Ottawa	Ontario	Canada	K1Y 4E9
83	McGill University Department of Oncology	Montreal	Quebec	Canada	H2W 1S6

Sponsors and Collaborators

• National Cancer Institute (NCI)
• Radiation Therapy Oncology Group

Investigators

• Principal Investigator: Paul Sperduto, Radiation Therapy Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00096265
• Other Study ID Numbers: NCI-2009-00720; NCI-2009-00720; CDR0000389490; RTOG 0320; RTOG 0320; RTOG-0320; U10CA021661
• First Posted: Nov 9, 2004
• Last Update Posted: Mar 9, 2018
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Neoplasms; Erlotinib Hydrochloride; Temozolomide

Study Results

Participant Flow

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
Period Title: Overall Study
STARTED	45	40	41
COMPLETED	44	40	41
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS	Total
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.	Total of all reporting groups
Overall Participants	45	40	41	126
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	63	61	63
Sex: Female, Male (Count of Participants)
Female	22 48.9%	18 45%	18 43.9%	58 46%
Male	23 51.1%	22 55%	23 56.1%	68 54%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Survival time is defined as time from randomization to date of death from any cause and estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact.
Time Frame	From randomization to date of death or last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

Outcome Measure Data

Analysis Population Description

All eligible patients.

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
Measure Participants	44	40	41
Median (95% Confidence Interval) [months]	13.4	6.3	6.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Temozolomide + WBRT + SRS
	Comments	120 patients per arm required to detect a 33% reduction in hazard rate corresponding to improvement in MST of 5.9 (null hypothesis) to 8.9 months with a one-sided type I error rate of 0.025 and 85% power.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments	One-sided
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; 0.89 to 2.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	WBRT + SRS is the denominator of the hazard ratio.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Erlotinib + WBRT + SRS
	Comments	120 patients per arm required to detect a 33% reduction in hazard rate corresponding to improvement in MST of 5.9 (null hypothesis) to 8.9 months with a one-sided type I error rate of 0.025 and 85% power.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.95
	Comments	One-sided
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.47
	Confidence Interval	(2-Sided) 95%; 0.92 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	WBRT + SRS is the denominator of the hazard ratio.

2. Secondary Outcome

Title	Rate of CNS Progression (One Year)
Description	CNS progression is defined as any increase in perpendicular bi-dimensional tumor area for any of the 1-3 tracked brain metastases, by any amount, or the appearance of any new brain metastasis on a follow-up MRI (SRS planning scan will not be used to evaluate CNS progression). For lesions smaller than 1 cm in maximum diameter, a maximum increase of 50% in perpendicular bi-dimensional treatment area is necessary to score as progression. This caveat is included to account for potential variability in measurement, which is most susceptible to proportionate errors at smaller sizes. For greater than 1 cm lesions, the definition uses a 25% rule for change. Rates of CNS progression estimated by the cumulative incidence method, with death treated as a competing risk.
Time Frame	From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
Measure Participants	44	40	41
Number (95% Confidence Interval) [percentage of participants]	34.1 75.8%	47.4 118.5%	27.4 66.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Temozolomide + WBRT + SRS
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	Gray's test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Temozolomide + WBRT + SRS, Erlotinib + WBRT + SRS
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments
	Method	Gray's test
	Comments

3. Secondary Outcome

Title	Quality-adjusted Survival as Measured by EuroQol 5-dimension Instrument
Description	Quality-adjusted life years (QALY) incorporate the societal-based utilities of health states into expected life years for a health condition. The QALY model is QALY(h,y) where h is a health state and y is the years of life. Higher quality-adjusted life year values represent a better outcome. A patient's health state will be determined from the index score of the EQ-5D-5L patient questionnaire.The EQ-5D-5L is a 2-part self-assessment questionnaire, a 5-item index score and a visual analogue scale, but only the index score is used for quality-adjusted survival. The index score has 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state).
Time Frame	From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

Outcome Measure Data

Analysis Population Description

Eligible patients with any follow-up EQ-5D

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
Measure Participants	24	19	18
Mean (Standard Deviation) [Quality-adjusted life years]	16.9 (9.6)	15.9 (12.0)	14.4 (12.5)

4. Secondary Outcome

Title	Change in Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 Months
Description	The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score, which ranges from 0 to 76. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-Br including the FACT-G must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicates better QOL. A change of 5 points will be considered a minimal clinically meaningful change. Change from baseline at three months (3 month score - baseline score) will be categorized as improvement if increased, stable if no change, or deterioration if decreased.
Time Frame	From randomization to three months.

Outcome Measure Data

Analysis Population Description

Eligible patients with both baseline and 3 month data

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
Measure Participants	26	16	17
Deterioration/Decrease	12 26.7%	10 25%	11 26.8%
Stable	8 17.8%	2 5%	6 14.6%
Improvement/Increase	6 13.3%	4 10%	1 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Temozolomide + WBRT + SRS
	Comments	With 70 patients per arm, a 0.05 level chi-square test would have 80% power to distinguish between two groups when the proportions in the three categories are as follows for standard vs. experimental arm, respectively: 25% vs. 50% improvement, 55% vs. 40% stable, and 20% vs. 10% deterioration, or any distribution that corresponds to an effect size, Δ² = Σ(π2j-π1j)2/[2(π2j-π1j)], of 0.0702.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Erlotinib + WBRT + SRS
	Comments	With 70 patients per arm, a 0.05 level chi-square test would have 80% power to distinguish between two groups when the proportions in the three categories are as follows for standard vs. experimental arm, respectively: 25% vs. 50% improvement, 55% vs. 40% stable, and 20% vs. 10% deterioration, or any distribution that corresponds to an effect size, Δ² = Σ(π2j-π1j)2/[2(π2j-π1j)], of 0.0702.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Change in Performance Status at Six Months
Description	Compared between two treatment arms using a two-group chi-squared test. Zubrod score will be collected at baseline and follow-up. The Zubrod performance score runs from 0 to 5, with 0 denoting perfect health and 5 death. Change from baseline is calculated as 6-month value - baseline value. Patients with a baseline score who have died by six months will be included in the analysis with a score of 5 at six months.
Time Frame	From randomization to six months.

Outcome Measure Data

Analysis Population Description

Eligible patients with baseline and 6 month data

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
Measure Participants	40	35	35
Improvement (decrease)	0 0%	1 2.5%	3 7.3%
Stable (no change)	19 42.2%	4 10%	2 4.9%
Deterioration (increase)	21 46.7%	30 75%	30 73.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Temozolomide + WBRT + SRS
	Comments	108 with three month performance status data, per arm, would result in a 0.050 level chi-square test with 90% power to distinguish between the groups when the proportions in the 3 categories are characterized by an effect size, Δ² = Σ(π2j-π1j)2/[2(π2j-π1j)], of 0.0586.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Erlotinib + WBRT + SRS
	Comments	108 cases with three month performance status data, per arm, would result in a 0.050 level chi-square test with 90% power to distinguish between the groups when the proportions in the 3 categories are characterized by an effect size, Δ² = Σ(π2j-π1j)2/[2(π2j-π1j)], of 0.0586.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Change in Steroid Dependence at Six Months
Description	Daily steroid dose will be collected at baseline and follow-up, as one of the following: 0-4 mg, >4 to ≤ 8 mg, >8 to ≤12 mg, and >12 mg. Change from baseline at six months will be evaluated to have decreased, remained stable, or increased, based on these categories.
Time Frame	From randomization to six months.

Outcome Measure Data

Analysis Population Description

Eligible patients with both baseline and 6 month steroid dose

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
Measure Participants	26	18	17
Decrease	12 26.7%	10 25%	10 24.4%
Stable	10 22.2%	4 10%	6 14.6%
Increase	4 8.9%	4 10%	1 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Temozolomide + WBRT + SRS
	Comments
	Type of Statistical Test	Superiority
	Comments	Assuming the survival rate of the standard arm (MST = 5.9 months), then 49% of patients were expected to be alive at six months. Assuming steroid data would be available for 90% of these patients, results in a projection of 52 cases/arm with steroid data at 6 months. With this sample size, a two-sided 0.050 alpha test will have 90% power to distinguish between the groups when the proportions in the 3 categories are characterized by an effect size, Δ² = Σ(π2j-π1j)2/[2(π2j-π1j)], of 0.1217.
Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Erlotinib + WBRT + SRS
	Comments	Assuming the survival rate of the standard arm (MST = 5.9 months), then 49% of patients were expected to be alive at six months. Assuming steroid data would be available for 90% of these patients, results in a projection of 52 cases/arm with steroid data at 6 months. With this sample size, a two-sided 0.050 alpha test will have 90% power to distinguish between the groups when the proportions in the 3 categories are characterized by an effect size, Δ² = Σ(π2j-π1j)2/[2(π2j-π1j)], of 0.1217.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.56
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Cause of Death (Neurologic vs Other)
Description	Patients were considered to have died neurologic deaths (coded as "Brain Metastases") if they had stable systemic disease and progressive neurologic disease consisting of expanding intracranial masses, CNS hemorrhages, hydrocephalus resulting in herniation or fulminant meningeal carcinomatosis.
Time Frame	From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

Outcome Measure Data

Analysis Population Description

Eligible patients who died

Arm/Group Title	WBRT + SRS	Temozolomide + WBRT + SRS	Erlotinib + WBRT + SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
Measure Participants	35	34	36
Neuroligic death	6 13.3%	5 12.5%	7 17.1%
Other	29 64.4%	29 72.5%	29 70.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Temozolomide + WBRT + SRS
	Comments	A two group chi-square test with a 0.05 two-sided significance level would have 89% power to detect the difference between a proportion of 0.50 and a proportion of 0.30, or equivalently, of 0.70, when the sample size in each group is 120.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	WBRT + SRS, Erlotinib + WBRT + SRS
	Comments	A two group chi-square test with a 0.05 two-sided significance level would have 89% power to detect the difference between a proportion of 0.50 and a proportion of 0.30, or equivalently, of 0.70, when the sample size in each group is 120.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.80
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Adverse Event Reporting Description	Per the protocol, toxicity data was collected via CTC 3.0 then mapped to CTCAE 4.0 for reporting on this website. Subjects experiencing more than one of a given adverse event (AE) are counted only once for that AE.
Arm/Group Title	WBRT+SRS		Temozolomide+WBRT+SRS		Erlotinib+WBRT+SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery. [Data is reported for eligible patients with adverse event information, which is 44 patients.]		Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. [Data is reported for eligible patients with adverse event information, which is 39 patients.]		Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months. [Data is reported for eligible patients with adverse event information, which is 41 patients.]
All Cause Mortality
	WBRT+SRS		Temozolomide+WBRT+SRS		Erlotinib+WBRT+SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	WBRT+SRS		Temozolomide+WBRT+SRS		Erlotinib+WBRT+SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/44 (22.7%)		22/39 (56.4%)		12/41 (29.3%)
Blood and lymphatic system disorders
Anemia	2/44 (4.5%)		5/39 (12.8%)		4/41 (9.8%)
Blood and lymphatic system disorders - Other	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Hemolysis	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Cardiac disorders
Cardiac disorders - Other	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Myocardial infarction	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Gastrointestinal disorders
Abdominal pain	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Lower gastrointestinal hemorrhage	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Nausea	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Rectal hemorrhage	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Upper gastrointestinal hemorrhage	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Vomiting	0/44 (0%)		1/39 (2.6%)		1/41 (2.4%)
General disorders
Death NOS	3/44 (6.8%)		2/39 (5.1%)		2/41 (4.9%)
Edema limbs	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Fatigue	0/44 (0%)		0/39 (0%)		2/41 (4.9%)
Fever	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
General disorders and administration site conditions - Other	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Non-cardiac chest pain	1/44 (2.3%)		1/39 (2.6%)		0/41 (0%)
Sudden death NOS	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Infections and infestations
Infections and infestations - Other	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Lung infection	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Injury, poisoning and procedural complications
Dermatitis radiation	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Fracture	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Investigations
Creatinine increased	0/44 (0%)		1/39 (2.6%)		1/41 (2.4%)
GGT increased	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
INR increased	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Investigations - Other	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Platelet count decreased	0/44 (0%)		4/39 (10.3%)		2/41 (4.9%)
Weight loss	0/44 (0%)		1/39 (2.6%)		2/41 (4.9%)
White blood cell decreased	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Metabolism and nutrition disorders
Anorexia	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Dehydration	0/44 (0%)		1/39 (2.6%)		1/41 (2.4%)
Hyperglycemia	0/44 (0%)		2/39 (5.1%)		1/41 (2.4%)
Hyperkalemia	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Hypocalcemia	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Hypokalemia	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Hypomagnesemia	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Hyponatremia	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Musculoskeletal and connective tissue disorders
Chest wall pain	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Generalized muscle weakness	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Muscle weakness lower limb	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Nervous system disorders
Ataxia	0/44 (0%)		1/39 (2.6%)		1/41 (2.4%)
Central nervous system necrosis	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Cognitive disturbance	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Dizziness	1/44 (2.3%)		1/39 (2.6%)		0/41 (0%)
Dysphasia	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Encephalopathy	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Headache	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Intracranial hemorrhage	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Ischemia cerebrovascular	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Leukoencephalopathy	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Peripheral motor neuropathy	0/44 (0%)		3/39 (7.7%)		0/41 (0%)
Peripheral sensory neuropathy	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Seizure	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Psychiatric disorders
Confusion	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Renal and urinary disorders
Renal and urinary disorders - Other	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Bronchopulmonary hemorrhage	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Bronchospasm	1/44 (2.3%)		1/39 (2.6%)		0/41 (0%)
Cough	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Dyspnea	0/44 (0%)		1/39 (2.6%)		2/41 (4.9%)
Hypoxia	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Pleural effusion	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Pneumonitis	0/44 (0%)		1/39 (2.6%)		1/41 (2.4%)
Respiratory, thoracic and mediastinal disorders - Other	2/44 (4.5%)		0/39 (0%)		0/41 (0%)
Skin and subcutaneous tissue disorders
Alopecia	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Rash maculo-papular	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Vascular disorders
Hypotension	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Thromboembolic event	0/44 (0%)		3/39 (7.7%)		3/41 (7.3%)
Other (Not Including Serious) Adverse Events
	WBRT+SRS		Temozolomide+WBRT+SRS		Erlotinib+WBRT+SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/44 (63.6%)		32/39 (82.1%)		34/41 (82.9%)
Blood and lymphatic system disorders
Anemia	7/44 (15.9%)		12/39 (30.8%)		11/41 (26.8%)
Blood and lymphatic system disorders - Other	0/44 (0%)		3/39 (7.7%)		0/41 (0%)
Disseminated intravascular coagulation	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Cardiac disorders
Atrial fibrillation	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Cardiac disorders - Other	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Myocardial infarction	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Sinus tachycardia	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Ear pain	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
External ear inflammation	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
External ear pain	0/44 (0%)		2/39 (5.1%)		1/41 (2.4%)
Hearing impaired	1/44 (2.3%)		2/39 (5.1%)		2/41 (4.9%)
Middle ear inflammation	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Endocrine disorders
Cushingoid	2/44 (4.5%)		1/39 (2.6%)		0/41 (0%)
Eye disorders
Blurred vision	1/44 (2.3%)		3/39 (7.7%)		1/41 (2.4%)
Conjunctivitis	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Dry eye	0/44 (0%)		1/39 (2.6%)		3/41 (7.3%)
Extraocular muscle paresis	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Eye disorders - Other	1/44 (2.3%)		1/39 (2.6%)		3/41 (7.3%)
Eye pain	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Optic nerve disorder	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Photophobia	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Watering eyes	1/44 (2.3%)		0/39 (0%)		1/41 (2.4%)
Gastrointestinal disorders
Abdominal distension	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Abdominal pain	1/44 (2.3%)		3/39 (7.7%)		1/41 (2.4%)
Constipation	3/44 (6.8%)		10/39 (25.6%)		10/41 (24.4%)
Dental caries	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Diarrhea	3/44 (6.8%)		3/39 (7.7%)		14/41 (34.1%)
Dry mouth	0/44 (0%)		2/39 (5.1%)		3/41 (7.3%)
Dyspepsia	0/44 (0%)		4/39 (10.3%)		1/41 (2.4%)
Dysphagia	2/44 (4.5%)		2/39 (5.1%)		3/41 (7.3%)
Fecal incontinence	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Flatulence	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Gastrointestinal disorders - Other	1/44 (2.3%)		0/39 (0%)		1/41 (2.4%)
Mucositis oral	0/44 (0%)		4/39 (10.3%)		2/41 (4.9%)
Nausea	7/44 (15.9%)		13/39 (33.3%)		15/41 (36.6%)
Oral hemorrhage	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Small intestinal obstruction	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Stomach pain	0/44 (0%)		1/39 (2.6%)		2/41 (4.9%)
Toothache	0/44 (0%)		1/39 (2.6%)		1/41 (2.4%)
Vomiting	6/44 (13.6%)		7/39 (17.9%)		8/41 (19.5%)
General disorders
Chills	1/44 (2.3%)		0/39 (0%)		1/41 (2.4%)
Edema face	2/44 (4.5%)		0/39 (0%)		1/41 (2.4%)
Edema limbs	2/44 (4.5%)		5/39 (12.8%)		2/41 (4.9%)
Fatigue	20/44 (45.5%)		24/39 (61.5%)		22/41 (53.7%)
Fever	0/44 (0%)		1/39 (2.6%)		2/41 (4.9%)
Gait disturbance	1/44 (2.3%)		3/39 (7.7%)		0/41 (0%)
General disorders and administration site conditions - Other	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Irritability	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Non-cardiac chest pain	2/44 (4.5%)		1/39 (2.6%)		5/41 (12.2%)
Pain	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Immune system disorders
Immune system disorders - Other	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Infections and infestations
Anorectal infection	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Bladder infection	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Enterocolitis infectious	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Infections and infestations - Other	1/44 (2.3%)		5/39 (12.8%)		5/41 (12.2%)
Lung infection	2/44 (4.5%)		0/39 (0%)		0/41 (0%)
Mucosal infection	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Otitis externa	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Otitis media	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Salivary gland infection	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Upper respiratory infection	0/44 (0%)		1/39 (2.6%)		2/41 (4.9%)
Urinary tract infection	0/44 (0%)		1/39 (2.6%)		1/41 (2.4%)
Injury, poisoning and procedural complications
Bruising	1/44 (2.3%)		1/39 (2.6%)		0/41 (0%)
Dermatitis radiation	2/44 (4.5%)		10/39 (25.6%)		4/41 (9.8%)
Fracture	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Radiation recall reaction (dermatologic)	0/44 (0%)		1/39 (2.6%)		2/41 (4.9%)
Investigations
Activated partial thromboplastin time prolonged	1/44 (2.3%)		1/39 (2.6%)		2/41 (4.9%)
Alanine aminotransferase increased	1/44 (2.3%)		4/39 (10.3%)		8/41 (19.5%)
Alkaline phosphatase increased	3/44 (6.8%)		4/39 (10.3%)		6/41 (14.6%)
Aspartate aminotransferase increased	1/44 (2.3%)		3/39 (7.7%)		10/41 (24.4%)
Blood bilirubin increased	0/44 (0%)		0/39 (0%)		4/41 (9.8%)
Creatinine increased	0/44 (0%)		1/39 (2.6%)		3/41 (7.3%)
Fibrinogen decreased	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
GGT increased	3/44 (6.8%)		1/39 (2.6%)		3/41 (7.3%)
INR increased	0/44 (0%)		4/39 (10.3%)		3/41 (7.3%)
Investigations - Other	0/44 (0%)		3/39 (7.7%)		2/41 (4.9%)
Lymphocyte count decreased	1/44 (2.3%)		2/39 (5.1%)		3/41 (7.3%)
Neutrophil count decreased	1/44 (2.3%)		2/39 (5.1%)		5/41 (12.2%)
Platelet count decreased	2/44 (4.5%)		7/39 (17.9%)		4/41 (9.8%)
Weight gain	2/44 (4.5%)		1/39 (2.6%)		0/41 (0%)
Weight loss	3/44 (6.8%)		8/39 (20.5%)		11/41 (26.8%)
White blood cell decreased	2/44 (4.5%)		3/39 (7.7%)		4/41 (9.8%)
Metabolism and nutrition disorders
Acidosis	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Anorexia	7/44 (15.9%)		13/39 (33.3%)		18/41 (43.9%)
Dehydration	0/44 (0%)		1/39 (2.6%)		5/41 (12.2%)
Hyperglycemia	4/44 (9.1%)		7/39 (17.9%)		7/41 (17.1%)
Hyperkalemia	0/44 (0%)		4/39 (10.3%)		0/41 (0%)
Hypermagnesemia	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Hypernatremia	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Hypoalbuminemia	3/44 (6.8%)		5/39 (12.8%)		8/41 (19.5%)
Hypocalcemia	4/44 (9.1%)		6/39 (15.4%)		6/41 (14.6%)
Hypoglycemia	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Hypokalemia	2/44 (4.5%)		4/39 (10.3%)		6/41 (14.6%)
Hypomagnesemia	1/44 (2.3%)		0/39 (0%)		2/41 (4.9%)
Hyponatremia	5/44 (11.4%)		4/39 (10.3%)		8/41 (19.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/44 (0%)		2/39 (5.1%)		2/41 (4.9%)
Back pain	3/44 (6.8%)		5/39 (12.8%)		3/41 (7.3%)
Bone pain	1/44 (2.3%)		3/39 (7.7%)		2/41 (4.9%)
Chest wall pain	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Generalized muscle weakness	3/44 (6.8%)		2/39 (5.1%)		5/41 (12.2%)
Muscle weakness left-sided	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Muscle weakness lower limb	3/44 (6.8%)		2/39 (5.1%)		3/41 (7.3%)
Muscle weakness right-sided	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Myalgia	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Neck pain	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Osteoporosis	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Pain in extremity	1/44 (2.3%)		1/39 (2.6%)		2/41 (4.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/44 (2.3%)		0/39 (0%)		1/41 (2.4%)
Nervous system disorders
Arachnoiditis	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Ataxia	3/44 (6.8%)		4/39 (10.3%)		4/41 (9.8%)
Central nervous system necrosis	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Cognitive disturbance	1/44 (2.3%)		2/39 (5.1%)		2/41 (4.9%)
Depressed level of consciousness	2/44 (4.5%)		0/39 (0%)		2/41 (4.9%)
Dizziness	4/44 (9.1%)		4/39 (10.3%)		6/41 (14.6%)
Dysgeusia	2/44 (4.5%)		4/39 (10.3%)		8/41 (19.5%)
Dysphasia	2/44 (4.5%)		2/39 (5.1%)		2/41 (4.9%)
Facial nerve disorder	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Headache	8/44 (18.2%)		8/39 (20.5%)		7/41 (17.1%)
Hydrocephalus	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Intracranial hemorrhage	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Ischemia cerebrovascular	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Memory impairment	5/44 (11.4%)		2/39 (5.1%)		6/41 (14.6%)
Myelitis	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Nervous system disorders - Other	2/44 (4.5%)		3/39 (7.7%)		1/41 (2.4%)
Peripheral motor neuropathy	4/44 (9.1%)		6/39 (15.4%)		4/41 (9.8%)
Peripheral sensory neuropathy	4/44 (9.1%)		2/39 (5.1%)		5/41 (12.2%)
Pyramidal tract syndrome	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Seizure	2/44 (4.5%)		4/39 (10.3%)		0/41 (0%)
Syncope	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Tremor	1/44 (2.3%)		2/39 (5.1%)		2/41 (4.9%)
Psychiatric disorders
Agitation	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Anxiety	2/44 (4.5%)		2/39 (5.1%)		2/41 (4.9%)
Confusion	4/44 (9.1%)		2/39 (5.1%)		6/41 (14.6%)
Depression	2/44 (4.5%)		1/39 (2.6%)		4/41 (9.8%)
Insomnia	3/44 (6.8%)		5/39 (12.8%)		4/41 (9.8%)
Libido decreased	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Personality change	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Renal and urinary disorders
Bladder spasm	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Cystitis noninfective	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Hematuria	0/44 (0%)		0/39 (0%)		2/41 (4.9%)
Hemoglobinuria	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Proteinuria	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Renal and urinary disorders - Other	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Urinary frequency	1/44 (2.3%)		0/39 (0%)		2/41 (4.9%)
Urinary incontinence	3/44 (6.8%)		0/39 (0%)		1/41 (2.4%)
Urinary tract pain	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Reproductive system and breast disorders
Erectile dysfunction	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Vaginal hemorrhage	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Atelectasis	0/44 (0%)		0/39 (0%)		2/41 (4.9%)
Bronchospasm	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Cough	6/44 (13.6%)		9/39 (23.1%)		6/41 (14.6%)
Dyspnea	9/44 (20.5%)		4/39 (10.3%)		11/41 (26.8%)
Epistaxis	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Hiccups	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Hypoxia	1/44 (2.3%)		1/39 (2.6%)		1/41 (2.4%)
Pharyngolaryngeal pain	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Pleural effusion	0/44 (0%)		0/39 (0%)		2/41 (4.9%)
Pleuritic pain	1/44 (2.3%)		0/39 (0%)		1/41 (2.4%)
Pneumonitis	0/44 (0%)		1/39 (2.6%)		3/41 (7.3%)
Respiratory, thoracic and mediastinal disorders - Other	0/44 (0%)		2/39 (5.1%)		0/41 (0%)
Voice alteration	0/44 (0%)		2/39 (5.1%)		1/41 (2.4%)
Skin and subcutaneous tissue disorders
Alopecia	5/44 (11.4%)		11/39 (28.2%)		7/41 (17.1%)
Dry skin	1/44 (2.3%)		1/39 (2.6%)		2/41 (4.9%)
Hyperhidrosis	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Nail loss	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Pain of skin	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Palmar-plantar erythrodysesthesia syndrome	0/44 (0%)		0/39 (0%)		2/41 (4.9%)
Pruritus	3/44 (6.8%)		2/39 (5.1%)		3/41 (7.3%)
Purpura	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Rash acneiform	2/44 (4.5%)		1/39 (2.6%)		12/41 (29.3%)
Rash maculo-papular	0/44 (0%)		0/39 (0%)		5/41 (12.2%)
Scalp pain	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Skin and subcutaneous tissue disorders - Other	2/44 (4.5%)		1/39 (2.6%)		1/41 (2.4%)
Skin hyperpigmentation	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Skin hypopigmentation	0/44 (0%)		0/39 (0%)		1/41 (2.4%)
Vascular disorders
Hypertension	1/44 (2.3%)		0/39 (0%)		0/41 (0%)
Hypotension	0/44 (0%)		3/39 (7.7%)		1/41 (2.4%)
Thromboembolic event	2/44 (4.5%)		3/39 (7.7%)		1/41 (2.4%)
Vascular disorders - Other	0/44 (0%)		1/39 (2.6%)		0/41 (0%)
Vasculitis	0/44 (0%)		0/39 (0%)		1/41 (2.4%)

Limitations/Caveats

This study stopped accrual early due to unmet targeted accrual goals with 126 subjects accrued out of 381 planned.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.