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

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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:
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
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
Hide 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
Arm/Group Title Whole Brain Irradiation and Temozolomide Whole Brain Irradiation Total
Hide 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
Hide 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
1.Primary Outcome
Title Objective Response Rates. Assessed With Cranial MRI
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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)
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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.
Hide 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
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Hide 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
Hide 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
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
Hide 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   --/--      --/--    
Show Serious Adverse Events Hide 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
Show Other (Not Including Serious) Adverse Events Hide 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
Our study had methodological limitations, such as the two temozolomide dose levels, which in future clinical trials may be adjusted to a single level.
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
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