Brain Neoplasms
Conditions
Keywords
Brain metastases, Temozolomide, Whole-brain radiotherapy, Phase II trial
Brief summary
RATIONALE * Fractionated radiotherapy uses high-energy photons to kill, or damage tumor cells. High daily dose temozolomide combined with fractionated radiotherapy may make tumor cells more sensible to treatment. PURPOSE * This randomized phase II trial, assess in patients with brain metastases from solid tumors, whether the whole brain radiotherapy (WBRT) plus temozolomide is able to improve the results obtained with WBRT.
Detailed description
Primary Outcome Measures * Objective Response Rates Secondary Outcome Measures * Survival Free of Brain Metastases progression * Overall Survival * Systemic Side effects Objectives Primary * Compare objective response rates in both arms of treatment Secondary * Compare survival free of progression in both arms of treatment * Compare Overall Survival in both arms of treatment * Compare side effects
Interventions
DRUGTemozolomide
RADIATIONWhole brain irradiation
Sponsors
Instituto Nacional de Cancerologia de Mexico
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Karnofsky performance status (KPS) ≥ 50 * Life expectancy ≥ 12 weeks * Histologically confirmed non lymphomatous solid tumors at primary site * Brain metastases diagnosed with cranial MRI/CT. * Extracranial metastases or primary tumor uncontrolled are allowed * Hemoglobin ≥ 10 g/dl * Absolute neutrophil count of \> 1500/mm3 * Platelet count of ≥ 100,000/mm3 * Blood urea nitrogen (BUN) ≤ 25 mg/dl, * Serum creatinin ≤ 1.5 mg/dl * Serum bilirubins ≤ 1.5 mg/dl, * Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ twice the upper normal limit
Exclusion criteria
* Pregnant or breast feeding woman * History of allergic reaction to iodinated contrast media * Inability to swallow * Systemic chemotherapy in previous 3 weeks * Oral chemotherapy in previous 2 weeks * Prior surgery, chemotherapy, or radiotherapy for a brain neoplasm * Meningeal carcinomatosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rates. Assessed With Cranial MRI | 90 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival Free of Brain Metastases Progression (PFS of BM) | at 90 days | 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. |
| Overall Survival | 1 year | Overall survival:Time in months measured from treatment initiation until the date of death or the date of last follow-up. |
| Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | 4 months | 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. |
Countries
Mexico
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.
Participants by arm
| Arm | Count |
|---|---|
| Whole Brain Irradiation and Temozolomide 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. | 28 |
| Whole Brain Irradiation Whole brain irradiation, 1 fraction of 3 Gy x 5 days each week for 2 weeks, Monday to Friday. | 27 |
| Total | 55 |
Baseline characteristics
| Characteristic | Whole Brain Irradiation | Whole Brain Irradiation and Temozolomide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 3 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 25 Participants | 44 Participants |
| Age Continuous | 53.8 years STANDARD_DEVIATION 13.7 | 49.5 years STANDARD_DEVIATION 13.4 | 51.7 years STANDARD_DEVIATION 13.55 |
| Region of Enrollment Mexico | 27 participants | 28 participants | 55 participants |
| Sex: Female, Male Female | 22 Participants | 25 Participants | 47 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 28 | 13 / 27 |
| serious Total, serious adverse events | 17 / 28 | 7 / 27 |
Outcome results
Primary
Objective Response Rates. Assessed With Cranial MRI
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
Population: Data on all enrolled participants were included in an intention-to-treat analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Whole Brain Irradiation and Temozolomide | Objective Response Rates. Assessed With Cranial MRI | 78.6 Percentage of participants with OR |
| Whole Brain Irradiation | Objective Response Rates. Assessed With Cranial MRI | 48.1 Percentage of participants with OR |
p-value: 0.01995% CI: [1.3, 12.9]Chi-squared
Secondary
Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment.
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Whole Brain Irradiation and Temozolomide | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Leukopenia | 1 Events |
| Whole Brain Irradiation and Temozolomide | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Nausea-Vomiting | 1 Events |
| Whole Brain Irradiation and Temozolomide | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Lymphopenia | 11 Events |
| Whole Brain Irradiation and Temozolomide | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Neutropenia | 1 Events |
| Whole Brain Irradiation and Temozolomide | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Platelets | 3 Events |
| Whole Brain Irradiation | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Neutropenia | 1 Events |
| Whole Brain Irradiation | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Platelets | 0 Events |
| Whole Brain Irradiation | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Leukopenia | 0 Events |
| Whole Brain Irradiation | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Lymphopenia | 6 Events |
| Whole Brain Irradiation | Number of Grade 3-4 Adverse Events (AE) That Are Definitely or Probably Related to Both Groups of Treatment. | Nausea-Vomiting | 0 Events |
Secondary
Overall Survival
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
Population: Data on all enrolled participants were included in an intention-to-treat analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Whole Brain Irradiation and Temozolomide | Overall Survival | 8 Months of Overall Survival |
| Whole Brain Irradiation | Overall Survival | 8.1 Months of Overall Survival |
p-value: 0.84Log Rank
Secondary
Survival Free of Brain Metastases Progression (PFS of BM)
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
Population: Data on all enrolled participants were included in an intention-to-treat analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Whole Brain Irradiation and Temozolomide | Survival Free of Brain Metastases Progression (PFS of BM) | 88.7 Percentage of Participants |
| Whole Brain Irradiation | Survival Free of Brain Metastases Progression (PFS of BM) | 83.7 Percentage of Participants |
p-value: 0.70495% CI: [0.138, 3.422]Fisher Exact