Hypofractionated Brain Radiation In EGFR Mutated Adenocarcinoma Cranial Disease (Hybrid)

Study Overview
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Brief Summary
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A multi-center phase III randomized controlled study to evaluate the efficacy of Hypofractionated SRS (HFSRS) along with EGFR-TKI in patients with brain metastasis from non-small cell lung cancer (NSCLC). Assuming that HFSRS is not inferior to EGFR-TKI concurrent with whole brain radiotherapy (WBRT), the primary end point is intracranial PFS (iPFS), while secondary outcomes included overall survival (OS), evaluation of cognitive function, quality of life (QoL) and adverse events.

Detailed Description
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WBRT remains to be standard of care for NSCL patients. Long term survival from WBRT may have noticeable cognitive dysfunction. The EGFR TKI has reasonable control for intracranial disease, but the duration of EGFR TKI control disease is variable due to tendency of drug resistance. To maintain intracranial disease control and improve cognitive function, the investigators propose using hypofractionated SRS in multiple brain metastases or large brain lesions alone with TKI.

Official Title
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Comparing Whole Brain Radiation With Hypofractionated Stereotactic RadioSurgery (HFSRS) in Patients With NSCL Brain Metastases

Conditions
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Stage IV EGFR Mutated NSCL With Brain Metastases

Intervention / Treatment
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* Drug: Gefitinib 250mg po qd or Tarceva 150mg po qd or Icotinib 125mg po tid Other Name: Gefitinib/Tarceva/Icotinib
* Radiation: WBRT
* Radiation: HFSRS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmation of non-small cell lung cancer (NSCLC); Diagnosis of brain metastases on a Gadolinium-enhanced MRI. More than 3 sites of intracranial metastases, or the longest diameter of the intracranial lesion is more than 4 cm. Positive EGFR mutation. Life expectancy ≥3months. Have one or more measurable encephalic lesions according to RECIST. Adequate hematological function: Absolute neutrophil count (ANC) ≥1.5 x 109/L, and Platelet count ≥100 x 109/L. Adequate renal function: Serum creatinine ≤1.5 x ULN, or ≥ 50 ml/min. Adequate liver function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) and Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 2.5 x ULN in the absence of liver metastases, or < 5 x ULN in case of liver metastases. Female subjects should not be pregnant. All human subjects should able to comply with the required protocol and follow-up procedures, and able to receive oral medications. Written informed consent provided. Exclusion Criteria: Previous usage of EGFR-TKI or antibody to EGFR: gefitinib, erlotinib, herceptin, erbitux. CSF or MRI findings consistent with metastases of spinal cord, meninges or meningeal. Allergic to Icotinib. Lack of physical integrity of the upper gastrointestinal tract, or malabsorption syndrome, or inability to take oral medication, or have active peptic ulcer disease. Pregnancy or breast-feeding women. Participate in the other anti-tumor clinical trials in 4 weeks.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: WBRT along with TKI<br>Drug: EGFR-TKI Gefitinib 250mg po qd or Tarceva 150mg po qd or Icotinib 125mg po tid Other Name: Gefitinib/Tarceva/Icotinib Radiation: whole brain radiotherapy 3750Gy/15F Other Name: WBRT | Drug: Gefitinib 250mg po qd or Tarceva 150mg po qd or Icotinib 125mg po tid Other Name: Gefitinib/Tarceva/Icotinib<br>* radiation given along with one of kind TKI<br>* Other names: EGFR-TKI;Radiation: WBRT<br>* 3750 cGy in 15 fractions given within 3 weeks time.<br>|
| Experimental: HFSRS with EGFR TKI<br>Drug: EGFR-TKI Gefitinib 250mg po qd or Tarceva 150mg po qd or Icotinib 125mg po tid Other Name: Gefitinib/Tarceva/Icotinib Radiation: whole brain radiotherapy 25 to 40 Gy/5F Other Name: HFSRS | Drug: Gefitinib 250mg po qd or Tarceva 150mg po qd or Icotinib 125mg po tid Other Name: Gefitinib/Tarceva/Icotinib<br>* radiation given along with one of kind TKI<br>* Other names: EGFR-TKI;Radiation: HFSRS<br>* All HFSRS given in 5 fractions. dose per fraction ranges from 5 to 8 Gy depending on the target volume and organs at risk tolerance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| iPFS | intracranial progression-free survival | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cognitive function | Neurocognitive effects evaluated according to Mini-Mental Status Examination Evaluated according to Mini-Mental Status Examination | 18 month | 
| Overall survival (OS) | Overall survival | 18 months |