A randomized phase II trial to assess the efficacy and safety of selective metabolically adaptive radiation dose escalation in locally advanced non-small cell lung cancer receiving definitive chemoradiotherapy. Eligible and consenting patients will be randomized to receive conventional chemoradiotherapy or chemoradiotherapy with a radiation (RT) integrated boost. All patients will receive a fludeoxyglucose-positron emission tomography (FDG-PET) scan within two weeks prior to starting treatment. The primary outcome is to determine if dose escalation to metabolically active tumor subvolumes will reduce local-regional failure rate at 2 years.

Inclusion Criteria:

• Patients who are at least 18 years old and are able to consent
• Patients who will undergo Chemo-RT as primarily modality of treatment
• Patients with a primary tumor or node measuring at least 10mm on CT scan
• Patients with a PET avid tumor having Standardized Uptake Values (SUV) > 4
• Patients with Eastern Cooperative Oncology Group (ECOG) status 0-2 within 4 weeks of randomization

Exclusion Criteria:

• Trimodality patients who have surgery as part of curative treatment
• Previous radiotherapy to intended treatment volumes
• Active invasive malignancy other than lung cancer
• Active pregnancy
• Poor respiratory function (Forced Expiratory Volume < 1.0 or Diffusing Capacity < 50% age-adjusted normal)
• ECOG status > 2
• Pre-treatment complete blood count/differential showing inadequate bone marrow reserve (absolute neutrophil count < 1800 cells/mm3 or platelets < 100 000 cells/mm3 or hemoglobin < 90g/L), measured within 4 weeks of registration
• AST, ALT or total bilirubin > 2.5 times the upper limit of normal, measured within 4 weeks of registration
• Unintentional weight loss >10% over 3 months within 4 weeks of registration
• Severe active co-morbidity defined by:
• Significant history of uncontrolled cardiac disease; i.e. uncontrolled hypertension, unstable angina, myocardial infarction within the last 6 months, uncontrolled congestive heart failure, cardiomyopathy with decreased ejection fraction
• Transmural myocardial infection requiring intravenous antibiotics at the time of registration
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization
• Acquired immune deficiency syndrome (AIDS) based on the current Centre for Disease Control definition; note, however, that HIV testing is not required for entry into this protocol