Temozolomide and Radiation Therapy in Treating Patients With Brain Metastasis Secondary to Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs such as temozolomide may make the tumor cells more sensitive to radiation therapy. Combining temozolomide with radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving temozolomide together with whole-brain radiation therapy works in treating patients with brain metastasis secondary to non-small cell lung cancer.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the intracranial response rate in patients with brain metastasis secondary to non-small cell lung cancer treated with whole brain radiotherapy and temozolomide. Secondary Determine the time to radiological progression in patients treated with this regimen. Determine the time to neurological progression (confirmed by magnetic resonance imaging (MRI)) in patients treated with this regimen. Determine the overall survival of patients treated with this regimen. Determine the toxicity of this regimen in these patients. OUTLINE: This is a multicenter study. Patients undergo whole brain radiotherapy once daily, 5 days a week, for 2 weeks (10 fractions). Patients also receive concurrent oral temozolomide once daily on days 1-14. Beginning 3 weeks after the completion of chemoradiotherapy, patients receive oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of neurologic (Central Nervous System, CNS) progression or unacceptable toxicity. Patients were followed every 3 months for 2 years. ACCRUAL: A total of 26 patients were accrued for this study.

Official Title
-----------------
A Phase II Study of Temozolomide and Radiation Therapy in Patients With Brain Metastasis From Non-small Cell Lung Cancer (NSCLC)

Conditions
-----------------
Lung Cancer, Metastatic Cancer

Intervention / Treatment
-----------------
* Drug: Temozolomide
* Radiation: Radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed non-small cell lung cancer (NSCLC), including the following histologies: Squamous cell carcinoma Adenocarcinoma Large cell carcinoma Bronchoalveolar carcinoma All variants of NSCLC At least 1 bidimensionally measurable brain metastasis Confirmed by MRI within the past two weeks, and computed tomography (CT) scan is not acceptable Biopsy is not required Not eligible for surgical resection or radiosurgery of brain metastasis Systemic disease not in immediate need of chemotherapy Age>=18 years ECOG Performance status of 0-1 More than 12 weeks of life expectancy Adequate hematologic, renal, and liver function as demonstrated by laboratory values performed within two weeks, inclusive, prior to administration of study drug or registration Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10 g/dL Bilirubin ≤ 2 times upper limit of normal (ULN) Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2 times upper limit of normal (5 times ULN if liver metastases are present) Alkaline phosphatase ≤ 2 times ULN (5 times ULN if liver metastases are present) Creatinine ≤ 1.6 mg/dL Fertile patients must use effective contraception Prior biologic therapy allowed More than 4 weeks since prior chemotherapy Prior radiotherapy for local control or palliative therapy for painful bony lesions allowed Prior surgery for brain metastasis allowed At least 4 weeks since prior radiotherapy to ≥ 15% of bone marrow (2 weeks for < 15% of bone marrow) and recovered No prior radiotherapy to ≥ 50% of bone marrow Concurrent radiotherapy to painful bony lesions allowed provided no more than 15% of bone marrow is irradiated Exclusion Criteria: HIV positive AIDS-related illness Poor medical risks due to active nonmalignant systemic disease Frequent vomiting There is medical condition that would interfere with oral medication intake (e.g., partial bowel obstruction) Pregnant or nursing Prior temozolomide Prior radiotherapy to the brain, including stereotactic radiosurgery to a different lesion Concurrent intensity modulated radiotherapy or 3-D cranial radiotherapy Other concurrent investigational agents Other concurrent treatment for brain metastasis Other concurrent chemotherapy during study radiotherapy Concurrent growth factors to induce elevations in blood counts for the purposes of administration of study drug at scheduled dosing interval or to allow treatment with study drug at a higher dose

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temozolomide and Radiation<br>Temozolomide:administered orally. Radiation: whole brain radiation therapy | Drug: Temozolomide<br>* Temozolomide (TMZ) to be given at a dose of 75 mg/m2/day for 14 days, starting on D1 of whole brain radiotherapy (WBRT). Three weeks after completion of WBRT, TMZ will be given at a dose of 200 mg/m2/day x 5 days (or 150 mg/m2/day if prior chemotherapy) every 28-days,for an additional two cycles.<br>* Other names: Temodar;Radiation: Radiation therapy<br>* Standard whole brain radiation therapy 30 Gy in ten fractions.<br>* Other names: Whole brain radiation therapy;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Intracranial Response | Response was assessed per Response Evaluation Criteria in Solid Tumor (RECIST) by brain MRI in the 21 eligible and treated patients.Complete response (CR): complete disappearance of the clinically detectable malignant brain metastasis(es) being followed on MRI scan off corticosteroids and a stable or improving neurologic exam. Partial response (PR): greater than or equal to a 50% reduction in the sum of the product(s) of the maximal cross-sections on MRI scan with a stable or decreasing dose of corticosteroids and a stable or improving neurologic exam. Response = CR + PR | assessed every cycle while on treatment, then every 3 months for 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-year Neurologic (Central Nervous System, CNS) Progression Free Rate | 1-year CNS progression free rate is the percentage of patients who had no CNS progression after being followed for 1 year . Progressive disease (CNS) was defined as a 25% or greater increase in the sum of the product(s) of the maximal cross-sections on MRI scan, reappearance of any lesion that has disappeared, development of any new lesion(s), stable disease with a deterioration of neurologic exam, or clear worsening of any evaluable disease. | assessed every 3 months for 2 years | 
| Time to Non-CNS (Systemic) Progression | Time to non-CNS progression was calculated from time of protocol entry to time of first systemic progressive disease or death. Patients alive and non-CNS progression-free at last follow-up were censored. Disease progression was defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter (per RECIST criteria). Development of new lesions in non-CNS sites also constituted non-CNS progression. The 21 eligible and treated patients were included in the analysis. | assessed every 3 months for 2 years | 
| Overall Survival Time | Overall survival (months) was calculated from time of protocol entry to time of death from any cause. Patients alive at last follow-up were censored. The 21 eligible and treated patients were included in the analysis. | assessed every 3 months for 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
recurrent non-small cell lung cancer, stage IV non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma of the lung, large cell lung cancer, bronchoalveolar cell lung cancer, adenosquamous cell lung cancer, tumors metastatic to brain