Surgery and/or Radiation Therapy or Standard Therapy and/or Clinical Observation in Treating Patients With Previously Treated Stage IV Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well surgery and/or radiation therapy or standard therapy and/or clinical observation works in treating patients with previously treated stage IV non-small cell lung cancer. Radiation therapy uses high energy x-rays to kill tumor cells. Giving surgery and/or radiation therapy may be more effective than standard therapy and/or clinical observation in patients with previously treated non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine whether oligometastatic non-small cell lung cancer (NSCLC) patients with no disease progression after first line therapy have prolonged progression free survival (PFS) when treated with local consolidation therapy (LCT) of residual disease (radiation or surgery) followed by maintenance or surveillance as per physician choice compared with no LCT. SECONDARY OBJECTIVES: I. Determine the overall survival. II. Safety/tolerability of LCT. III. Time to progression of prior metastatic lesions. IV. Time to appearance of new metastases (central nervous system [CNS] vs. extra-CNS, treated lesion vs. new site). V. Quality of life (QOL). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I (IMMEDIATE LCT): Patients undergo ablation of all residual local and metastatic sites of disease by surgery and/or external beam radiation therapy (EBRT). After completion of LCT, patients undergo either surveillance or maintenance treatment at the discretion of the treating physician. ARM II (DELAYED/NO LCT): Patients undergo standard maintenance therapy or clinical observation, based on physician choice. Patients may cross-over to Arm I due to Response Evaluation Criteria in Solid Tumors (RECIST) progression or toxicity at the treating physician's discretion. After completion of study treatment, patients are followed up for 9 months.

Official Title
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A Randomized Phase II Study Assessing the Efficacy of Local Consolidative Therapy for Non-Small Cell Lung Cancer Patients With Induced Oligometastatic Disease

Conditions
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Recurrent Lung Non-Small Cell Carcinoma, Stage IV Non-Small Cell Lung Cancer AJCC v7

Intervention / Treatment
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* Other: Clinical Observation
* Radiation: External Beam Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment
* Procedure: Standard Follow-Up Care
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: STEP 1 ENROLLMENT: the patient has a diagnosis of pathologically confirmed NSCLC by tumor biopsy and/or fine-needle aspiration; mixed tumors will be categorized by the predominant cell type STEP 1 ENROLLMENT: the patient has a diagnosis of American Joint Committee on Cancer (AJCC) 7th Edition stage IV NSCLC STEP 1 ENROLLMENT: three or less metastatic lesions (not sites); each lesion (including a satellite nodule) will individually be counted as one, and intrathoracic lymph node involvement (defined here as hilar, mediastinal, or supraclavicular nodes, N1-N3) will collectively be counted as one; in addition, patients can receive treatment to CNS lesions or other symptomatic lesions requiring urgent local therapy prior to randomization, but these lesions will be counted towards the total number after chemotherapy, and patients will only be eligible if there are remaining sites amenable to local therapy after up-front systemic therapy STEP 1 ENROLLMENT: standard induction chemotherapy planned defined as: at least 4 cycles of platinum doublet chemotherapy for metastatic disease (with or without bevacizumab); if the patient is known to be EGFR mutation positive, erlotinib, afatinib, or gefitinib for >= 3 months, or for patients with known EML4-ALK fusions, crizotinib for >= 3 months STEP 2 ENROLLMENT AND RANDOMIZATION: the patient has a diagnosis of pathologically confirmed NSCLC by tumor biopsy and/or fine-needle aspiration; mixed tumors will be categorized by the predominant cell type STEP 2 ENROLLMENT AND RANDOMIZATION: the patient has a diagnosis of American Joint Committee on Cancer (AJCC) 7th edition stage IV NSCLC STEP 2 ENROLLMENT AND RANDOMIZATION: completion of standard induction chemotherapy planned defined as: at least 4 cycles of platinum doublet chemotherapy for metastatic disease (with or without bevacizumab); if the patient is known to be EGFR mutation positive, erlotinib, afatinib, or gefitinib for >= 3 months, or for patients with known EML4-ALK fusions, crizotinib; note that it is not mandatory to check EGFR mutation or EML4-ALK status prior to entry, but patients that receive options 2 or 3 should have had these molecular tests performed STEP 2 ENROLLMENT AND RANDOMIZATION: less than or equal to three metastatic lesions and no evidence of disease progression based on RECIST criteria; note that patients that had > 3 metastatic lesions in Step 1 may be eligible for enrollment in Step 2 if the number of metastatic sites is reduced to three or less STEP 2 ENROLLMENT AND RANDOMIZATION: the patient's Eastern Cooperative Oncology Group (ECOG) performance status is =< 2 at study entry STEP 2 ENROLLMENT AND RANDOMIZATION: absolute neutrophil count (ANC) >= 1,500/mm^3 within 3 weeks of study entry STEP 2 ENROLLMENT AND RANDOMIZATION: platelet count >= 100,000/mm^3 within 3 weeks of study entry STEP 2 ENROLLMENT AND RANDOMIZATION: white blood cells (WBC) >= 3,000/mm^3 within 3 weeks of study entry STEP 2 ENROLLMENT AND RANDOMIZATION: hemoglobin >= 9 g/dL within 3 weeks of study entry STEP 2 ENROLLMENT AND RANDOMIZATION: the patient must be a suitable candidate for LCT (radiotherapy and/or surgery) to every site of disease, as determined by the treating physician(s); consultation with a multidisciplinary team, including a medical oncologist, radiation oncologist, and thoracic surgeon, is encouraged but not required STEP 2 ENROLLMENT AND RANDOMIZATION: concurrent chemoradiation is permitted as consolidative therapy; the following concurrent therapies are permitted: tyrosine kinase inhibitors (i.e. erlotinib) - can be delivered with both hypofractionated (>= 3 Gray [Gy] per fraction) and standard fractionated radiation therapy (< 3 Gy per fraction); platinum-based chemotherapy - standard fractionated radiation therapy (< 3 Gy per fraction) STEP 2 ENROLLMENT AND RANDOMIZATION: bevacizumab will not be permitted within 2 weeks of the initiation of the radiation therapy course STEP 2 ENROLLMENT AND RANDOMIZATION: treatment to central nervous system lesions, such as the brain or spine (prior to first line systemic therapy), or symptomatic lesions requiring urgent palliative radiation, is permitted prior to randomization, in which case the patient would be randomized to treatment of other metastatic sites or the primary sites (based on the disease remaining after first-line treatment); these treated lesions should be counted towards the total number of metastases at the time of enrollment STEP 2 ENROLLMENT AND RANDOMIZATION: the patient has signed informed consent STEP 2 ENROLLMENT AND RANDOMIZATION: women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for six (6) months after discontinuation of the study drugs; childbearing potential will be defined as women who have had menses within the past 12 months, who have not had tubal ligation, hysterectomy or bilateral oophorectomy; should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately; the patient, if a man, agrees to use effective contraception or abstinence for the duration of study participation and for six (6) months after discontinuation of the study drugs Exclusion Criteria: STEPS 1 AND 2 AND RANDOMIZATION The patient has a history of uncontrolled angina, arrhythmias, or congestive heart failure Patients with a history of malignant pleural effusions are not eligible; pleural effusions considered by the investigator too small for a diagnostic thoracentesis are permissible Patient is pregnant (confirmed by serum beta- b-human chorionic gonadotropin [HCG] if applicable) or is breastfeeding Presence of significant third space fluid which cannot be controlled by drainage

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (immediate LCT)<br>Patients undergo ablation of all residual local and metastatic sites of disease by surgery and/or EBRT. After completion of LCT, patients undergo either surveillance or maintenance treatment at the discretion of the treating physician. | Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: external-beam radiation;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|
| Active Comparator: Arm II (delayed/no LCT)<br>Patients undergo standard maintenance therapy or clinical observation, based on physician choice. Patients may cross-over to Arm I due to RECIST progression or toxicity at the treating physician's discretion. | Other: Clinical Observation<br>* Undergo clinical observation<br>* Other names: observation;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Procedure: Standard Follow-Up Care<br>* Undergo standard maintenance therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Kaplan-Meier estimate will be computed and the log-rank test will be performed to compare the difference of PFS between the two arms. Cox regression model will be applied to correlate PFS with potential covariates in both the univariate and multi-covariate analyses. To account for patients that crossover for reasons other than Response Evaluation Criteria in Solid Tumors (RECIST) progression of disease, censoring will occur at the time of crossover for primary analysis. | Time from randomization (immediate local consolidation therapy [LCT] vs delayed/no LCT) to disease progression or death, assessed up to 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicities | Descriptive statistics will be provided to summarize the toxicities by the treatment arms (immediate LCT and delayed/no LCT groups). | Up to at least 1 year (periodically thereafter) | 
| Overall survival | Kaplan-Meier estimate will be used. | Up to 9 months | 
| Time to progression of prior metastatic lesions | Kaplan-Meier estimate will be used. | Up to 9 months | 
| Time to appearance of new metastases (central nervous system [CNS] vs extra-CNS, treated lesion vs. new site) | Kaplan-Meier estimate will be used. | Up to 9 months | 
| Quality of life (QOL) assessed using the Symptom Assessment (optional) | QOL will be analyzed by the repeated measures analysis of variance to count for the change before and after treatment and during the follow-up period. Proper transformation will be performed if necessary to transform data to be closer to the Gaussian distribution. | Up to 1 year | 
| Impact of crossover without RECIST progression | A time varying covariate model will be used. | Up to 9 months |