Platinum Doublet Chemotherapy and Proton Beam Radiation Therapy in Treating Patients With Stage II-III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well platinum doublet chemotherapy and proton beam radiation therapy work in treating patients with stage II-III non-small cell lung cancer that cannot be removed by surgery (unresectable). Drugs used in chemotherapy, such as carboplatin, paclitaxel, etoposide, cisplatin, and pemetrexed work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy protons to kill tumor cells and shrink tumors. Giving platinum doublet chemotherapy and proton beam radiation therapy may work better in treating patients with non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the 1-year progression-free survival rates of 72 gray (Gy) and 60 Gy conventionally fractionated proton beam therapy (PBT) (as part of concurrent combined modality therapy). SECONDARY OBJECTIVES: I. To assess the adverse events, survival, quality of life, and patterns of failure (local regional, distant metastatic) associated with two dose levels of conventionally fractionated PBT (as part of concurrent combined modality therapy). OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive platinum based doublet chemotherapy consisting of low dose carboplatin and paclitaxel, standard etoposide cisplatin or carboplatin or standard pemetrexed with cisplatin or carboplatin weekly for up to 6 weeks at the discretion of the treating medical oncologist. Patients also undergo lower dose proton beam radiation therapy daily for a total of 60 Gy for up to 30 weekdays in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive platinum based doublet chemotherapy consisting of low dose carboplatin and paclitaxel, standard etoposide cisplatin or carboplatin or standard pemetrexed with cisplatin or carboplatin weekly for up to 6 weeks at the discretion of the treating medical oncologist. Patients also undergo higher dose proton beam radiation therapy daily for a total of 72 Gy for up to 36 weekdays in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 3 years and then every 6 months for 2 years.

Official Title
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Phase II Trial of Standard Platinum Doublet Chemotherapy + Various Proton Beam Therapy (PBT) Doses in Order to Determine the Optimal Dose of PBT for Unresectable Stage 2/3 Non-Small Cell Lung Cancer

Conditions
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Recurrent Lung Non-Small Cell Carcinoma, Stage II Lung Non-Small Cell Cancer AJCC v7, Stage IIA Lung Non-Small Cell Carcinoma AJCC v7, Stage IIB Lung Non-Small Cell Carcinoma AJCC v7, Stage III Lung Non-Small Cell Cancer AJCC v7, Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7, Unresectable Lung Non-Small Cell Carcinoma

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Etoposide
* Drug: Paclitaxel
* Drug: Pemetrexed
* Radiation: Proton Beam Radiation Therapy
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Histological confirmation of non-small cell lung cancer Forced expiratory volume in 1 second (FEV1) > 1.0 L Unresectable or medically inoperable stage 2-3 non-small cell lung cancer (based on computed tomography/positron emission tomography [CT/PET], magnetic resonance imaging [MRI] or CT of brain, and physical exam); Eligible if recurrence after surgery and now has the equivalent stage 2-3 non-small cell lung cancer (NSCLC) OR had sub totally resected stage 2-3 NSCLC Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only White blood cell (WBC) >= 3.0 x 10^9/L Absolute neutrophil count (ANC) >= 1.5 x 10^9/L Hemoglobin (Hgb) >= 9 g/dl Platelets (plts) > 100 x 10^9/L Serum creatinine < 1.5 x upper limits of normal (ULN) Serum bilirubin < 1.5 x ULN Provide informed written consent Willing to return to enrolling institution for follow-up for a minimum of 1 year Ability to undergo potentially curative chemotherapy plus radiotherapy Exclusion Criteria: Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Weight loss of > 10% in the past 3 months Distant metastases (M1 disease) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, lupus, usual interstitial pneumonitis (UIP), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Receiving any investigational agent, that would be considered as a treatment for the primary neoplasm Active second malignancy History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias Received chemotherapy for lung cancer within 6 months of registration Previous chest radiotherapy that would overlap with the proton field

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (platinum doublet chemotherapy, lower dose PBT)<br>Patients receive platinum based doublet chemotherapy consisting of low dose carboplatin and paclitaxel, standard etoposide cisplatin or carboplatin or standard pemetrexed with cisplatin or carboplatin weekly for up to 6 weeks at the discretion of the treating medical oncologist. Patients also undergo lower dose proton beam radiation therapy daily for a total of 60 Gy for up to 30 weekdays in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Chemotherapy<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Chemotherapy<br>* Other names: Platosin;Drug: Etoposide<br>* Chemotherapy<br>* Other names: VP16;Drug: Paclitaxel<br>* Chemotherapy<br>* Other names: Taxol Konzentrat;Drug: Pemetrexed<br>* Chemotherapy<br>* Other names: Pemfexy;Radiation: Proton Beam Radiation Therapy<br>* Undergo PBT<br>* Other names: Radiation, Proton Beam;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm C (platinum doublet chemotherapy, higher dose PBT)<br>Patients receive platinum based doublet chemotherapy consisting of low dose carboplatin and paclitaxel, standard etoposide cisplatin or carboplatin or standard pemetrexed with cisplatin or carboplatin weekly for up to 6 weeks at the discretion of the treating medical oncologist. Patients also undergo higher dose proton beam radiation therapy daily for a total of 72 Gy for up to 36 weekdays in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Chemotherapy<br>* Other names: Ribocarbo;Drug: Paclitaxel<br>* Chemotherapy<br>* Other names: Taxol Konzentrat;Radiation: Proton Beam Radiation Therapy<br>* Undergo PBT<br>* Other names: Radiation, Proton Beam;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | A Cox proportional hazards model stratified by stratification factors will be used to model PFS as a function of dose to test for an overall dose effect (a one-sided p-value < 0.10 will be considered as significant evidence of a dose effect). Subsequently, separate Cox models stratified by stratification factors will compare PFS between 72 Gy and 60 Gy (for each, a one-sided p-value < 0.10 will be considered as significant evidence of superiority). Kaplan Meier estimates and curves by dose level will also be generated | From randomization to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will be modeled using Cox models. Kaplan-Meier estimates and curves by dose level will also be generated. OS will again be analyzed as exploratory analysis after 50 deaths per primary pairwise comparison have occurred or after all patients have completed follow-up (whichever occurs first). | From randomization to death due to any cause, assessed up to 5 years | 
| Incidence of adverse events | Graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns by dose level (60, 72 Gy). Additionally, the relationship of the adverse event(s) to dose level will be taken into consideration. | Up to 5 years | 
| Local-regional failure | Defined as the time from randomization to the earliest date of documentation of local recurrence. The cumulative incidence of local failure will be estimated using Gray's methodology and compared across dose levels using Fine-Gray quadratic regression (with death as a competing risk). | Up to 5 years | 
| Distant metastasis | Defined as the time from randomization to the earliest date of documentation of distant metastasis. The cumulative incidence of distant metastasis will be estimated using Gray's methodology and compared across dose levels using Fine-Gray quadratic regression (with death as a competing risk). | Up to 5 years |