Breast Cancer, Cognitive/Functional Effects, Lung Cancer, Metastatic Cancer, Prostate Cancer
Conditions
Keywords
cognitive/functional effects, tumors metastatic to brain, stage IV breast cancer, stage IV prostate cancer, stage IV non-small cell lung cancer, male breast cancer, recurrent breast cancer, recurrent prostate cancer, recurrent non-small cell lung cancer
Brief summary
RATIONALE: Stereotactic radiation therapy can send x-rays directly to the tumor and cause less damage to normal tissue. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether stereotactic radiation therapy is more effective with or without whole-brain radiation therapy in treating patients with brain metastases. PURPOSE: This randomized phase III trial is studying stereotactic radiation therapy and whole-brain radiation therapy to see how well they work compared with stereotactic radiation therapy alone in treating patients with brain metastases.
Detailed description
OBJECTIVES: Primary * Compare the overall survival of patients with 1 to 3 cerebral metastases treated with stereotactic radiosurgery with vs without whole-brain radiotherapy. Secondary * Compare time to CNS (brain) failure in patients treated with these regimens. * Compare quality of life, duration of functional independence, and long-term neurocognitive status of patients treated with these regimens. * Compare post-treatment toxicity in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (18 to 59 vs 60 and over), extracranial disease (controlled for ≤ 3 months vs controlled for \> 3 months), and number of brain metastases (1 vs 2 vs 3). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients undergo stereotactic radiosurgery (SRS). * Arm II: Patients undergo SRS as in arm I. Within 14 days, patients then undergo whole-brain radiotherapy 5 days a week for 2.5 weeks. Quality of life, functional independence, and neurocognitive status are assessed at baseline, at the beginning of each treatment, at weeks 6 and 12, and then at 6, 9, 12, 16, 24 , 36, 48, and 60 months. PROJECTED ACCRUAL: A total of 238 patients will be accrued for this protocol.
Interventions
RADIATIONradiation therapy
Patients undergo radiation therapy 5 days a week for 2.5 weeks
RADIATIONstereotactic radiosurgery
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of cerebral metastases meeting the following criteria: * One to three presumed brain metastases * Metastases must be from a histologically confirmed extracerebral site (e.g., lung, breast, prostate) * Histologic confirmation may have been from the primary tumor site, from another metastatic site (e.g., osseous metastasis, adrenal metastasis), or from the metastatic brain lesion(s) * Each lesion must measure less than 3.0 cm by contrast MRI of the brain performed within the past 21 days * Lesions must not be within 5 mm of the optic chiasm or within the brainstem * Eligibility for treatment with gamma knife or linear accelerator-based radiosurgery confirmed by a radiation oncologist * No primary germ cell tumor, small cell carcinoma, or lymphoma * No leptomeningeal metastases * Hormone receptor status not specified PATIENT CHARACTERISTICS: * Male or female * Menopausal status not specified * ECOG performance status 0-2 * Not pregnant * Negative pregnancy test * Fertile patients must use effective contraception * Male patients must continue to use contraception for 3 months after the completion of radiotherapy * No pacemaker or other MRI-incompatible metal in the body * No known allergy to gadolinium PRIOR CONCURRENT THERAPY: * More than 7 days since prior and no concurrent chemotherapy * No prior cranial radiotherapy * No prior resection of cerebral metastases * Concurrent hormonal agents, steroids, and/or anticonvulsants allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurocognitive Progression as Measured by the Number of Participants With Cognitive Deterioration by 3 Months | 3 months post radiosurgery | The primary endpoint was cognitive deterioration (progression), defined as a decline of greater than 1 SD from baseline on at least 1 of 7 cognitive tests (all tests are standardized based on published norms and transformed so that higher values represent improved cognition) at the 3-month post-SRS evaluation. The number of participants who experienced cognitive deterioration by 3 months is reported for each arm below. For primary analysis of the 3-month cognitive deterioration endpoint, the Fisher exact 2-group binomial test was used to compare the proportion of evaluable patients with 3-month cognitive deterioration between the 2 groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Local and Distant Tumor Control up to 3 Months | Up to 3 months | Number of Participants with Local and Distant Tumor Control up to 3 months is defined as.... |
| Overall Quality of Life, as Measured by Mean Change From Baseline [3 Month] | From Baseline to 3-Month Evaluation | Quality of Life was assessed using the Functional Assessment of Cancer Therapy-Brain, for which the range is from 0 to 200 and higher scores indicate better QOL. The Quality of Life (QOL) scores were transformed to a 0- to 100-point scale (with 100 being most favorable), in which a 10-point change was considered clinically significant. Intergroup changes in QOL scores were compared using a 2-sample t test. |
| Long-Term Neurocognitive Status (Long-Term Cognitive Status), as Measured by Percentage of Long-term Survivors With Cognitive Deterioration at 12 Months | From baseline to 12 months | Long-Term Neurocognitive Status \> To ascertain in patients with one to three brain metastases whether there is better long-term neurocognitive status in patients who receive SRS alone (Arm A) compared to patients who receive SRS combined with WBRT (Arm B). Long-term survival status is defined as evaluable patients who survived for at least 12 months and had at least one cognitive assessment on or after 365 days. |
| Overall Survival | Up to 5 years | Overall survival, defined as the time from randomization until death due to any cause, was compared between the groups using stratified log-rank tests. |
Countries
Canada, United States
Participant flow
Recruitment details
At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. 70 patients accrued by ACOSOG Z0300 were included in the power calculation and also included for this study.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (SRS) Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter. | 111 |
| Arm II (SRS+WBRT) Patients undergo stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) received 22 Gy in a single fraction if lesions were less than 2.0cm or 18 Gy if lesions were 2 to 2.9 cm in maximum diameter.\>
\> Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS. | 102 |
| Total | 213 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Cancellation | 1 | 0 |
| Overall Study | Death | 23 | 19 |
| Overall Study | Disability or language problem | 0 | 1 |
| Overall Study | Had follow-up <90 d | 3 | 6 |
| Overall Study | Ineligible | 0 | 1 |
| Overall Study | Other | 5 | 2 |
| Overall Study | Refused testing | 0 | 1 |
| Overall Study | Withdrawal by Subject | 16 | 24 |
Baseline characteristics
| Characteristic | Arm I (SRS) | Arm II (SRS+WBRT) | Total |
|---|---|---|---|
| Age, Continuous | 59.8 years STANDARD_DEVIATION 10.4 | 61.4 years STANDARD_DEVIATION 10.6 | 60.6 years STANDARD_DEVIATION 10.5 |
| Age, Customized 18 to 59 | 53 Participants | 44 Participants | 97 Participants |
| Age, Customized >= 60 | 58 Participants | 58 Participants | 116 Participants |
| Region of Enrollment Canada | 23 participants | 22 participants | 45 participants |
| Region of Enrollment United States | 88 participants | 80 participants | 168 participants |
| Sex: Female, Male Female | 57 Participants | 47 Participants | 104 Participants |
| Sex: Female, Male Male | 54 Participants | 55 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 68 | 7 / 64 |
| other Total, other adverse events | 45 / 68 | 53 / 64 |
| serious Total, serious adverse events | 8 / 68 | 11 / 64 |
Outcome results
Primary
Neurocognitive Progression as Measured by the Number of Participants With Cognitive Deterioration by 3 Months
The primary endpoint was cognitive deterioration (progression), defined as a decline of greater than 1 SD from baseline on at least 1 of 7 cognitive tests (all tests are standardized based on published norms and transformed so that higher values represent improved cognition) at the 3-month post-SRS evaluation. The number of participants who experienced cognitive deterioration by 3 months is reported for each arm below. For primary analysis of the 3-month cognitive deterioration endpoint, the Fisher exact 2-group binomial test was used to compare the proportion of evaluable patients with 3-month cognitive deterioration between the 2 groups.
Time frame: 3 months post radiosurgery
Population: Patients who died prior to the 3-month evaluation, who did not return for the 3-month evaluation or a subsequent evaluation, or who did not complete the required baseline tests were excluded from the analysis population for the primary end point.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (SRS) | Neurocognitive Progression as Measured by the Number of Participants With Cognitive Deterioration by 3 Months | 40 Participants |
| Arm II (SRS+WBRT) | Neurocognitive Progression as Measured by the Number of Participants With Cognitive Deterioration by 3 Months | 44 Participants |
p-value: <0.00190% CI: [-41.9, -14.4]Fisher Exact
Secondary
Long-Term Neurocognitive Status (Long-Term Cognitive Status), as Measured by Percentage of Long-term Survivors With Cognitive Deterioration at 12 Months
Long-Term Neurocognitive Status \> To ascertain in patients with one to three brain metastases whether there is better long-term neurocognitive status in patients who receive SRS alone (Arm A) compared to patients who receive SRS combined with WBRT (Arm B). Long-term survival status is defined as evaluable patients who survived for at least 12 months and had at least one cognitive assessment on or after 365 days.
Time frame: From baseline to 12 months
Population: Patients who survived for at least 12 months and had at least one cognitive assessment on or after 365 days were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (SRS) | Long-Term Neurocognitive Status (Long-Term Cognitive Status), as Measured by Percentage of Long-term Survivors With Cognitive Deterioration at 12 Months | 60 percentage of participants |
| Arm II (SRS+WBRT) | Long-Term Neurocognitive Status (Long-Term Cognitive Status), as Measured by Percentage of Long-term Survivors With Cognitive Deterioration at 12 Months | 94.44 percentage of participants |
p-value: 0.0495% CI: [-74.4, 5.5]Fisher Exact
Secondary
Number of Participants With Local and Distant Tumor Control up to 3 Months
Number of Participants with Local and Distant Tumor Control up to 3 months is defined as....
Time frame: Up to 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (SRS) | Number of Participants With Local and Distant Tumor Control up to 3 Months | 79 Participants |
| Arm II (SRS+WBRT) | Number of Participants With Local and Distant Tumor Control up to 3 Months | 89 Participants |
p-value: <0.00195% CI: [-29, -7.8]Fisher Exact
Secondary
Overall Quality of Life, as Measured by Mean Change From Baseline [3 Month]
Quality of Life was assessed using the Functional Assessment of Cancer Therapy-Brain, for which the range is from 0 to 200 and higher scores indicate better QOL. The Quality of Life (QOL) scores were transformed to a 0- to 100-point scale (with 100 being most favorable), in which a 10-point change was considered clinically significant. Intergroup changes in QOL scores were compared using a 2-sample t test.
Time frame: From Baseline to 3-Month Evaluation
Population: All patients in the SRS and SRS+WBRT groups that had a baseline and 3-month QOL score were used in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I (SRS) | Overall Quality of Life, as Measured by Mean Change From Baseline [3 Month] | -0.1 QOL score change from baseline points |
| Arm II (SRS+WBRT) | Overall Quality of Life, as Measured by Mean Change From Baseline [3 Month] | -12 QOL score change from baseline points |
p-value: 0.00195% CI: [4.8, 19]t-test, 2 sided
Secondary
Overall Survival
Overall survival, defined as the time from randomization until death due to any cause, was compared between the groups using stratified log-rank tests.
Time frame: Up to 5 years
Population: A survival comparison was performed on an intention-to-treat basis using the entire study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (SRS) | Overall Survival | 10.4 months |
| Arm II (SRS+WBRT) | Overall Survival | 7.4 months |
p-value: 0.9295% CI: [0.75, 1.38]Regression, Cox