Lung Cancer, Metastatic Cancer
Conditions
Keywords
recurrent non-small cell lung cancer, stage IV non-small cell lung cancer, tumors metastatic to brain
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving radiation therapy together with pemetrexed may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving whole-brain radiation therapy together with pemetrexed works in treating patients with brain metastases from non-small cell lung cancer.
Detailed description
OBJECTIVES: Primary * Estimate the response in patients with intracranial brain metastases from non-small cell lung cancer treated with whole-brain radiotherapy and pemetrexed disodium. Secondary * Determine the toxicity of this regimen in these patients. * Estimate the overall survival of patients treated with this regimen. * Evaluate the functional status of patients treated with this regimen. * Assess neurological function and progression in patients treated with this regimen. * Determine the response of patients with extracranial disease treated with pemetrexed disodium. OUTLINE: Patients undergo whole-brain radiotherapy 5 days a week for 3 weeks beginning on day 1. Patients also receive pemetrexed disodium IV on day 1, 2, or 3 and day 28 of course 1, and on day 1 of each subsequent course. Treatment with pemetrexed disodium repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 30 days and then every 2 months for 2 years.
Interventions
DRUGpemetrexed disodium
500 mg/m2 once every 21 days up to 126 days
RADIATIONradiation therapy
Patients will receive cranial irradiation at 2.5 Gy per fraction, 5 days a week, for 3 weeks to a total dose of 37.5 Gy
Sponsors
National Cancer Institute (NCI)
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) * Must have evidence of brain metastases by MRI or CT scan PRIOR CONCURRENT THERAPY: * Recovered from prior oncologic or major surgery * Prior resection of all brain metastases or only site of brain metastases allowed provided there is radiologically evaluable intracranial metastases * No prior cranial irradiation, including stereotactic radiosurgery * More than 30 days since prior non-approved or investigational drug * No other concurrent chemotherapy, immunotherapy, hormonal therapy, radiotherapy, surgery, or experimental medications * No single brain metastases or oligometastatic disease amenable to surgical resection or radiosurgery * Relapsed NSCLC with brain metastases allowed * Not a candidate for double-agent or platinum-based chemotherapy * No leptomeningeal metastases * No clinically relevant (defined by physical exam) pleural effusions or ascites that cannot be controlled with drainage or other procedures Inclusion Criteria: * Karnofsky performance status 70-100% OR ≥ 70 years of age * Life expectancy \> 3 months * Absolute neutrophil count (ANC) \> 1,500/mm³ * Platelet count \> 100,000/mm³ * Hemoglobin ≥ 8 g/dL * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 times upper limit of normal (ULN) * Bilirubin ≤ 1.5 times ULN * Creatinine clearance ≥ 45 mL/min * Able to take vitamins, folic acid, and corticosteroids
Exclusion criteria
* Contraindication or intolerance to corticosteroid therapy * Other malignancies within the past 5 years and disease-free OR prognosis is best defined by the NSCLC in the opinion of the attending physician * Pregnant or nursing * Positive pregnancy test * Fertile patients must use effective contraception * HIV positive * Severe hypersensitivity to pemetrexed disodium * Unable to discontinue NSAIDs for ≥ 5 days * History of underlying dementia, Parkinson's disease, or Alzheimer's disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response of Intracranial Metastases (Complete and Partial Response) | 126 days | Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing Adverse Events | maximum 5 months | Toxicities was assessed using Common Terminology Criteria for Adverse Events (CTCAE) grading scale. Only toxicities with attribution to chemotherapy of definite or probable are considered, as determined by treating physician. |
| Estimate the Overall Survival of Patients Treated With This Regimen. | 4 years | Patients were followed for survival from start of treatment until death from any cause (up to 4 years) |
| Evaluate the Functional Status of Patients Treated With This Regimen. | baseline functional status only | Functional status evaluated using the Karnofsky functional status scale. The Karnofsky Performance Scale (KPS) Index allows patients to be classified as to their functional impairment. This can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients. The lower the Karnofsky score, the worse the survival for most serious illnesses. The Karnofsky score runs from 100 to 0, where 100 is perfect health and 0 is death. |
| Neurological Function by Radiation Oncology Group (RTOG) Neurological Function Classification | At Baseline, 30 days, and at end of treatment (maximum 5 months). | A classification score defined as follows: 1. Able to work or to perform normal activities: neurological findings minor or absent 2. Able to carry out normal activities with minimal difficulties. Neurological impairment does not require nursing care or hospitalization 3. Seriously limited in performing normal activities. Requiring nursing care or hospitalization. Patients confined to bed or wheelchair or have significant intellectual impairment 4. Unable to perform even minimal normal activities. Requiring hospitalization and constant nursing care and feeding. Patients unable to communicate or in coma.A higher score indicates worse function. |
| Neurological Function by Mini Mental State Examination | Baseline (pre-treatment), 30 days (Cycle 2 Day 1), and maximum 5 months (end of treatment). | The Mini Mental State Examination is a 30-point questionnaire that is used to measure cognitive impairment. Score totals range from normal cognition (24-30 points), mild impairment (19-23 points), moderate impairment (10-18 points), to severe impairment (≤9 points). |
| Response of Patients With Extracranial Disease Treated With Pemetrexed | maximum 5 months | Response was measured by Response Evaluation Criteria In Solid Tumors RECIST criteria v1.0. Complete Response (CR) - Disappearance of all lesions Partial Response (PR) - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Stable Disease (SD) - neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. Progressive Disease (PD) - at least a 20% increase 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 lesions or unequivocal progression of existing nontarget lesions. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from 2 institutions between May 2005 and April 2008.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Study Single Arm Study
pemetrexed disodium: 500 mg/m2 once every 21 days up to 126 days
radiation therapy: Patients will receive cranial irradiation at 2.5 Gy per fraction, 5 days a week, for 3 weeks to a total dose of 37.5 Gy | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Decline in performance | 3 |
| Overall Study | Extra-cranial disease progression | 1 |
Baseline characteristics
| Characteristic | Single Arm Study |
|---|---|
| Age, Continuous | 62.5 years |
| Karnofsky Performance Status KPS 70-80; unable to carry on all normal activity | 6 Participants |
| Karnofsky Performance Status KPS 80-90; some symptoms of disease | 0 Participants |
| Karnofsky Performance Status KPS 90-100; minor symptoms of disease | 3 Participants |
| Karnofsky Performance Status KPS unknown | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 1 / 10 |
Outcome results
Primary
Response of Intracranial Metastases (Complete and Partial Response)
Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 126 days
Population: Of the 10 patients, four patients were unevaluable due to extra-cranial disease progression or decline in performance status prevent re-evaluation.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm Study | Response of Intracranial Metastases (Complete and Partial Response) | partial response | 1 Participants |
| Single Arm Study | Response of Intracranial Metastases (Complete and Partial Response) | stable disease | 3 Participants |
| Single Arm Study | Response of Intracranial Metastases (Complete and Partial Response) | progressive disease | 2 Participants |
Secondary
Estimate the Overall Survival of Patients Treated With This Regimen.
Patients were followed for survival from start of treatment until death from any cause (up to 4 years)
Time frame: 4 years
Population: Four patients were unevaluable due to extra-cranial disease progression or decline in performance status preventing re-evaluation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm Study | Estimate the Overall Survival of Patients Treated With This Regimen. | 6.0 months |
Secondary
Evaluate the Functional Status of Patients Treated With This Regimen.
Functional status evaluated using the Karnofsky functional status scale. The Karnofsky Performance Scale (KPS) Index allows patients to be classified as to their functional impairment. This can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients. The lower the Karnofsky score, the worse the survival for most serious illnesses. The Karnofsky score runs from 100 to 0, where 100 is perfect health and 0 is death.
Time frame: baseline functional status only
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm Study | Evaluate the Functional Status of Patients Treated With This Regimen. | KPS 90-100; minor symptoms of disease | 3 Participants |
| Single Arm Study | Evaluate the Functional Status of Patients Treated With This Regimen. | KPS 80-90; some symptoms of disease | 0 Participants |
| Single Arm Study | Evaluate the Functional Status of Patients Treated With This Regimen. | KPS 70-80; unable to carry on all normal activity | 6 Participants |
| Single Arm Study | Evaluate the Functional Status of Patients Treated With This Regimen. | KPS unknown | 1 Participants |
Secondary
Neurological Function by Mini Mental State Examination
The Mini Mental State Examination is a 30-point questionnaire that is used to measure cognitive impairment. Score totals range from normal cognition (24-30 points), mild impairment (19-23 points), moderate impairment (10-18 points), to severe impairment (≤9 points).
Time frame: Baseline (pre-treatment), 30 days (Cycle 2 Day 1), and maximum 5 months (end of treatment).
Population: This study was terminated due to slow enrollment and the planned statistical analyses could not be performed due to limited sample size. The data represents the results of patients enrolled and treated on the trial.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Single Arm Study | Neurological Function by Mini Mental State Examination | Pre-Treatment | 28 score on the scale |
| Single Arm Study | Neurological Function by Mini Mental State Examination | Cycle 2 Day 1 | 28.2 score on the scale |
| Single Arm Study | Neurological Function by Mini Mental State Examination | End of treatment | 27.7 score on the scale |
Secondary
Neurological Function by Radiation Oncology Group (RTOG) Neurological Function Classification
A classification score defined as follows: 1. Able to work or to perform normal activities: neurological findings minor or absent 2. Able to carry out normal activities with minimal difficulties. Neurological impairment does not require nursing care or hospitalization 3. Seriously limited in performing normal activities. Requiring nursing care or hospitalization. Patients confined to bed or wheelchair or have significant intellectual impairment 4. Unable to perform even minimal normal activities. Requiring hospitalization and constant nursing care and feeding. Patients unable to communicate or in coma.A higher score indicates worse function.
Time frame: At Baseline, 30 days, and at end of treatment (maximum 5 months).
Population: This study was terminated due to slow enrollment and the planned statistical analyses could not be performed due to limit sample size. The data represents the results of patients enrolled and treated on the trial.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Single Arm Study | Neurological Function by Radiation Oncology Group (RTOG) Neurological Function Classification | Pre-Treatment | 1.6 scores on a scale |
| Single Arm Study | Neurological Function by Radiation Oncology Group (RTOG) Neurological Function Classification | Cycle 2 | 1.9 scores on a scale |
| Single Arm Study | Neurological Function by Radiation Oncology Group (RTOG) Neurological Function Classification | End of Treatment | 2.2 scores on a scale |
Secondary
Number of Subjects Experiencing Adverse Events
Toxicities was assessed using Common Terminology Criteria for Adverse Events (CTCAE) grading scale. Only toxicities with attribution to chemotherapy of definite or probable are considered, as determined by treating physician.
Time frame: maximum 5 months
Population: All patients who received treatment were evaluated
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Anemia | 2 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Alpecia | 2 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Nausea | 6 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Anorexia | 1 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Pruritic rash on head | 1 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Cramps | 1 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Acute bronchitis | 1 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Blurred vision | 1 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Dry skin | 1 Participants |
| Single Arm Study | Number of Subjects Experiencing Adverse Events | Fatigue | 2 Participants |
Secondary
Response of Patients With Extracranial Disease Treated With Pemetrexed
Response was measured by Response Evaluation Criteria In Solid Tumors RECIST criteria v1.0. Complete Response (CR) - Disappearance of all lesions Partial Response (PR) - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Stable Disease (SD) - neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. Progressive Disease (PD) - at least a 20% increase 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 lesions or unequivocal progression of existing nontarget lesions.
Time frame: maximum 5 months
Population: This study was terminated due to slow enrollment and the planned statistical analyses could not be performed due to limit sample size. The data represents the results of patients enrolled and treated on the trial.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm Study | Response of Patients With Extracranial Disease Treated With Pemetrexed | partial response | 2 Participants |
| Single Arm Study | Response of Patients With Extracranial Disease Treated With Pemetrexed | stable disease | 3 Participants |
| Single Arm Study | Response of Patients With Extracranial Disease Treated With Pemetrexed | progressive disease | 1 Participants |
| Single Arm Study | Response of Patients With Extracranial Disease Treated With Pemetrexed | missing data | 4 Participants |