Whole Brain Radiotherapy With or Without Temozolomide at Daily Fixed-dose for Brain Metastases Treatment

• ClinicalTrials.gov Identifier: NCT01015534
• Recruitment Status: Completed
• First Posted: November 18, 2009
• Results First Posted: May 8, 2013
• Last Update Posted: May 8, 2013
• Sponsor: Instituto Nacional de Cancerologia de Mexico
• Information provided by (Responsible Party): Carlos Gamboa Vignolle, Instituto Nacional de Cancerologia de Mexico

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Brain Neoplasms
• Interventions: Drug: Temozolomide; Radiation: Whole brain irradiation
• Enrollment: 55

Participant Flow

Recruitment Details	Participants were recruited from patients from Instituto Nacional de Cancerología de México, from January 2006 to September 2008.
Pre-assignment Details	Seventy-two patients were assessed for eligibility. Twelve patients did not meet inclusion criteria. Five patients declined to participate. Fifty-five patients were enrolled.

Arm/Group Title	Whole Brain Irradiation and Temozolomide	Whole Brain Irradiation
Arm/Group Description	Whole brain irradiation, 1 fraction of 3 Gy x 5 days of each week for 2 weeks, Monday to Friday and a fixed dose of oral temozolomide, 1h before each daily fraction of Whole brain irradiation, 200 mg on Monday, Wednesday, Friday; 300 mg on Tuesday, and Thursday. Without extra cycles of Temozolomide.	Whole brain irradiation, 1 fraction of 3 Gy x 5 days each week for 2 weeks, Monday to Friday.
Period Title: Overall Study
Started	28	27
Completed	27	27
Not Completed	1	0

Baseline Characteristics

Arm/Group Title		Whole Brain Irradiation and Temozolomide	Whole Brain Irradiation	Total
Arm/Group Description		Whole brain irradiation, 1 fraction of 3 Gy x 5 days of each week for 2 weeks, Monday to Friday and a fixed dose of oral temozolomide, 1h before each daily fraction of Whole brain irradiation, 200 mg on Monday, Wednesday, Friday; 300 mg on Tuesday, and Thursday. Without extra cycles of Temozolomide.	Whole brain irradiation, 1 fraction of 3 Gy x 5 days each week for 2 weeks, Monday to Friday.	Total of all reporting groups
Overall Number of Baseline Participants		28	27	55
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	28 participants	27 participants	55 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	25 89.3%	19 70.4%	44 80.0%
	>=65 years	3 10.7%	8 29.6%	11 20.0%
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	28 participants	27 participants	55 participants
		49.5 (13.4)	53.8 (13.7)	51.7 (13.55)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	28 participants	27 participants	55 participants
	Female	25 89.3%	22 81.5%	47 85.5%
	Male	3 10.7%	5 18.5%	8 14.5%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Mexico	Number Analyzed	28 participants	27 participants	55 participants
		28	27	55

Outcome Measures

1. Primary Outcome

Title	Objective Response Rates. Assessed With Cranial MRI
Description	Objective Response (OR) encompassed the number of participants with Complete Response (CR) and the number of participants with Partial Response (PR). CR is the disappearance of all brain metastases, assessed between two or more cranial MRI. PR is at least a 30% decrease in the sum of the longest diameter of the brain metastases, taking as reference the baseline sum longest diameter, assessed between two or more cranial MRI. Objective Response Rate (ORR) is the ratio between the number of participants with objective response and the total number of participants.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Data on all enrolled participants were included in an intention-to-treat analysis.

Arm/Group Title	Whole Brain Irradiation and Temozolomide	Whole Brain Irradiation
Arm/Group Description:	Patients received Whole brain irradiation at a dose of 30 Gy in 10 daily fractions over 2 weeks, and a fixed dose of oral Temozolomide, 1h before each fraction of whole brain irradiation, 200 mg on Monday, Wednesday, Friday; 300 mg on Tuesday, and Thursday. Without adjuvant cycles of Temozolomide.	Whole brain irradiation,at a dose of 30 Gy in 10 daily fractions over 2 weeks
Overall Number of Participants Analyzed	28	27
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants with OR
	78.6; (63.4 to 93.8)	48.1; (29.2 to 66.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Whole Brain Irradiation and Temozolomide, Whole Brain Irradiation
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.019
	Comments	The sample size was calculated with a two-sided test,a type-I error probability of 0.05 and a power of 0.80,Twenty- eight patients in each treatment arm were required to detect a difference in ORR of 0.29
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; 1.3 to 12.9
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Survival Free of Brain Metastases Progression (PFS of BM)
Description	Progression free survival of brain metastases is the survival of participants without progressive brain metastases or without neurological symptoms. The progressive brain metastases (PBM) were evaluated with cranial MRI. The PBM were defined as an increase of at least 20% in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new metastases.
Time Frame	at 90 days

Outcome Measure Data

Analysis Population Description

Data on all enrolled participants were included in an intention-to-treat analysis.

Arm/Group Title	Whole Brain Irradiation and Temozolomide	Whole Brain Irradiation
Arm/Group Description:	Whole brain irradiation at a dose of 30 Gy in 10 daily fractions over 2 weeks, and a fixed dose of oral Temozolomide, 1h before each fraction of whole brain irradiation, 200 mg on Monday, Wednesday, Friday; 300 mg on Tuesday, and Thursday. Without adjuvant cycles of Temozolomide.	Whole brain irradiation, at a dose of 30 Gy in 10 daily fractions over 2 weeks
Overall Number of Participants Analyzed	28	27
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	88.7; (76.7 to 100)	83.7; (69 to 98.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Whole Brain Irradiation and Temozolomide, Whole Brain Irradiation
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.704
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	.688
	Confidence Interval	(2-Sided) 95%; .138 to 3.422
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival:Time in months measured from treatment initiation until the date of death or the date of last follow-up.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Data on all enrolled participants were included in an intention-to-treat analysis.

Arm/Group Title	Whole Brain Irradiation and Temozolomide	Whole Brain Irradiation
Arm/Group Description:	Whole brain irradiation at a dose of 30 Gy in 10 daily fractions over 2 weeks, and a fixed dose of oral Temozolomide, 1h before each fraction of whole brain irradiation, 200 mg on Monday, Wednesday, Friday; 300 mg on Tuesday, and Thursday. Without adjuvant cycles of Temozolomide.	Whole brain irradiation, at a dose of 30 Gy in 10 daily fractions over 2 weeks
Overall Number of Participants Analyzed	28	27
Median (95% Confidence Interval); Unit of Measure: Months of Overall Survival
	8; (4.9 to 11.1)	8.1; (5.9 to 10.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Whole Brain Irradiation and Temozolomide, Whole Brain Irradiation
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.84
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

4. Secondary Outcome

Title	Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment.
Description	AE, evaluated and graded according to the NCI common terminology criteria (NCI-CTCAE) v3.0 Grade 3 Severe AE. Grade 4 Life-threatening or disabling AE.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Participants were assessed with a Complete blood count at the end of the first and second weeks of treatment. A standard biochemical profile was performed at the end of the second week of treatment, at 2 weeks after completion and at 2 months thereafter. Participants also were evaluated clinically with the same periodicity .

Arm/Group Title	Whole Brain Irradiation and Temozolomide	Whole Brain Irradiation
Arm/Group Description:	Whole brain irradiation, Whole brain irradiation at a dose of 30 Gy in 10 daily fractions over 2 weeks,and a fixed dose of oral temozolomide, 1h before each daily fraction of Whole brain irradiation, 200 mg on Monday, Wednesday, Friday; 300 mg on Tuesday, and Thursday. Without extra cycles of Temozolomide.	Whole brain irradiation, at a dose of 30 Gy in 10 daily fractions over 2 weeks
Overall Number of Participants Analyzed	28	27
Measure Type: Number; Unit of Measure: Events
Leukopenia	1	0
Lymphopenia	11	6
Nausea-Vomiting	1	0
Neutropenia	1	1
Platelets	3	0

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	Patients were assessed as follows: with a Complete blood count at the end of the first and second week of treatment. A standard biochemical profile at the end of the second week of treatment, at 2 weeks after completion and at 2 months thereafter. Also were evaluated clinically with the same periodicity.
Arm/Group Title	Whole Brain Irradiation and Temozolomide		Whole Brain Irradiation
Arm/Group Description	Whole brain irradiation, 1 fraction of 3 Gy x 5 days of each week for 2 weeks, Monday to Friday and a fixed dose of oral temozolomide, 1h before each daily fraction of Whole brain irradiation, 200 mg on Monday, Wednesday, Friday; 300 mg on Tuesday, and Thursday. Without extra cycles of Temozolomide.		Whole brain irradiation, 1 fraction of 3 Gy x 5 days each week for 2 weeks, Monday to Friday.
All-Cause Mortality
	Whole Brain Irradiation and Temozolomide		Whole Brain Irradiation
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Whole Brain Irradiation and Temozolomide		Whole Brain Irradiation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/28 (60.71%)		7/27 (25.93%)
Blood and lymphatic system disorders
Lymphopenia † 1 [1]	11/28 (39.29%)	11	6/27 (22.22%)	6
Leukopenia † 1 [2]	1/28 (3.57%)	1	0/27 (0.00%)	0
Platelets † 1 [3]	3/28 (10.71%)	3	0/27 (0.00%)	0
Neutrophils † 1 [4]	1/28 (3.57%)	1	1/27 (3.70%)	1
Hepatobiliary disorders
Nausea-Vomiting † 1 [5]	1/28 (3.57%)	1	0/27 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, CTCAE (3.0); [1] Grade 3 <500 – 200 mm3. Grade 4 <200/mm3; [2] Grade 3 <2000 – 1000/mm3; [3] Grade 3 <50,000 – 25,000/mm3. Grade 4 <25,000/mm3; [4] Grade 3 <1000 – 500/mm3; [5] Grade 3 ≥6 episodes in 24 hrs; IV fluids, indicated ≥24 hrs
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	3.5%
	Whole Brain Irradiation and Temozolomide		Whole Brain Irradiation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/28 (39.29%)		13/27 (48.15%)
Blood and lymphatic system disorders
Lymphopenia † 1 [1]	5/28 (17.86%)	5	11/27 (40.74%)	11
platelets † 1 [2]	3/28 (10.71%)	3	1/27 (3.70%)	1
Metabolism and nutrition disorders
Alanine aminotransferase - Aspartate aminotransferase † 1 [3]	3/28 (10.71%)	3	1/27 (3.70%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, CTCAE (3.0); [1] Grade 1 < Low limit of normal (LLN) – 800/mm3. Grade 2 <800 – 500/mm3.; [2] Grade 1; [3] Alanine aminotransferase Grade 1 > Upper limit of normal (ULN) – 2.5 x ULN Aspartate aminotransferase Grade 1 > ULN – 2.5 x ULN

Limitations and Caveats

Our study had methodological limitations, such as the two temozolomide dose levels, which in future clinical trials may be adjusted to a single level.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Carlos Gamboa Vignolle/ Radiation Oncologist
• Organization: Instituto Nacional de Cancerologia de Mexico
• Phone: 0155556280400 ext 441
• EMail: cswgamboa@yahoo.com

Publications:

Jones SF, Greco FA, Gian VG, Miranda FT, Raefsky EL, Hainsworth JD, Willcutt NT, Beschorner AF, Kennerly G, Burris HA 3rd. A Phase I trial of protracted oral fixed-dose temozolomide. Cancer. 2005 Nov 1;104(9):1985-91.

Antonadou D, Paraskevaidis M, Sarris G, Coliarakis N, Economou I, Karageorgis P, Throuvalas N. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol. 2002 Sep 1;20(17):3644-50.

Verger E, Gil M, Yaya R, Viñolas N, Villà S, Pujol T, Quintó L, Graus F. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat Oncol Biol Phys. 2005 Jan 1;61(1):185-91.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gamboa-Vignolle C, Ferrari-Carballo T, Arrieta Ó, Mohar A. Whole-brain irradiation with concomitant daily fixed-dose temozolomide for brain metastases treatment: a randomised phase II trial. Radiother Oncol. 2012 Feb;102(2):187-91. doi: 10.1016/j.radonc.2011.12.004. Epub 2012 Jan 16.

• Responsible Party: Carlos Gamboa Vignolle, Instituto Nacional de Cancerologia de Mexico
• ClinicalTrials.gov Identifier: NCT01015534 History of Changes
• Other Study ID Numbers: 006/004/TEI
• First Submitted: November 17, 2009
• First Posted: November 18, 2009
• Results First Submitted: August 23, 2012
• Results First Posted: May 8, 2013
• Last Update Posted: May 8, 2013