Chemotherapy With or Without Bevacizumab in Treating Patients With Stage IB, Stage II, or Stage IIIA Non-Small Lung Cancer That Was Removed By Surgery

• Overall survival (OS) [ Time Frame: Time from randomization to death, assessed up to 10 years ] [ Designated as safety issue: No ]
  The primary comparison will be an intent-to-treat analysis including all randomized patients. The study design incorporates a group sequential testing plan using a truncated O'Brien-Fleming boundary function at an overall one-sided significance level of 0.025 for assessing the stratified logrank test at each interim analysis. The O'Brien-Fleming group sequential boundary adjusts for the sequential testing and the use function methodology of Lan and DeMets 1 will be employed to adjust the boundaries if the actual interim analyses do not correspond with the projected information times provided.
  
  

• Disease-free survival (DFS) [ Time Frame: Time from randomization to an event, assessed up to 10 years ] [ Designated as safety issue: No ]
  Intent to treat analysis per randomization will be conducted. Kaplan-Meier estimates of DFS will be calculated3. The comparison will be assessed by using stratified log-rank test.
  
  
• Toxicity as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 1 year post-treatment ] [ Designated as safety issue: Yes ]
  If the difference in the rate of a particular category of toxicities between the 2 arms (N=750 per arm) is at least 5% (4% vs. 9%), 96% power can be attained assuming a significance level of 5% (two-sided Chi Square test) and that the lower toxicity rate for one arm is 4%. A difference in the rates of grade 3-5 arterial thromboembolic events (ATE) and bleeding events will be monitored and assessed between the treatment arms.
  
  
• Correlation between VEGF and ICAM expression and clinical outcomes (OS and DFS) by gene expression analysis and immunohistochemistry [ Time Frame: From baseline to up to 15 months ] [ Designated as safety issue: No ]
  Stratified log-rank test to assess whether the difference in the expression level of VEGF/ICAM predict survival at each time-point will be used. A Cox regression model to further determine how VEGF/ICAM expression levels predict survival outcome controlling for other important covariates such as treatment type, age, gender, stage, performance status and smoking status at each time point. Longitudinal techniques will be used to assess whether the ICAM expression levels in the blood differ in the two treatment arms over time
  
  
• Correlation between smoking status and OS assessed by the Smoking Status Survey [ Time Frame: From baseline to up to 1 year ] [ Designated as safety issue: No ]
  Descriptive and summary statistics will be conducted on the smoking questionnaire data.
  
  

PRIMARY OBJECTIVES:

I. Compare overall survival of patients with completely resected stage IB (tumors ≥ 4cm)-IIIA non-small cell lung cancer treated with adjuvant chemotherapy with or without bevacizumab.

SECONDARY OBJECTIVES:

I. Compare disease-free survival of patients treated with these regimens. II. Compare the toxicity of these regimens in these patients. III. Perform analyses of tissue and blood to establish factors that predict clinical outcome in patients treated with these regimens.

IV. Determine whether smoking status is linked to outcome in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to type of chemotherapy (cisplatin/vinorelbine ditartrate vs cisplatin/docetaxel vs cisplatin/gemcitabine hydrochloride vs cisplatin/pemetrexed disodium), stage (IB vs II vs IIIA [N2] vs IIIA [T3, N1]), histology (squamous cell vs other), and gender. Patients are randomized to 1 of 2 treatment arms.

ARM I (adjuvant chemotherapy without bevacizumab): Patients receive 1 of 4 chemotherapy regimens.

REGIMEN 1: Patients receive vinorelbine ditartrate IV over 10 minutes on days 1 and 8 and cisplatin IV over 60 minutes on day 1 immediately following vinorelbine ditartrate administration.

REGIMEN 2: Patients receive docetaxel IV over 1 hour on day 1 and cisplatin over 1 hour on day 1 immediately following docetaxel administration.

REGIMEN 3: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and cisplatin IV over 60 minutes on day 1 immediately following gemcitabine administration.

REGIMEN 4 (non-squamous histology only): Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 1 hour on day 1 immediately following pemetrexed disodium administration.

In all regimens, treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II (adjuvant chemotherapy with bevacizumab): Patients receive chemotherapy as in arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab repeats every 21 days for up to 1 year. Patients complete smoking status questionnaires at baseline and then every 3 months during study treatment.

After completion of study treatment, patients are followed periodically for 10 years.